WINTER

CONFERENCE
ON
BRAIN
RESEARCH

BIG SKY, MONTANA

BIG SKY RESORT
JANUARY 25-30, 2020
 ge
Lod ky
The Big S
at

by
Sunken Lob

Board Room
(3rd Floor)

Basecamp
Andiamo Italian Grille
(1st Floor)

i-ranch
(2nd Floor)

Montana
Walking Path
Jack
(1st Floor)

Lone Peak Pavilion

(summer only)
WELCOME TO THE 2020 WINTER
CONFERENCE ON BRAIN RESEARCH (WCBR).
This year is our 53rd annual meeting, and we are pleased to return to Big Sky, a
favorite venue for excellent science and outstanding skiing. We are excited about
the lineup of scientific and networking activities that will be offered during the
conference. Please note that the conference is back to our usual schedule with the
opening reception on Saturday, January 25, 2020 and the concluding banquet on
Thursday, January 30, 2020.
The opening scientific presentation of the conference will be a plenary lecture
during breakfast on Sunday, January 26th. Our speaker is Gregory W. Albers,
MD, a Professor in the Department of Neurology and Neurological Sciences, and
the Department of Neurosurgery at the Stanford University School of Medicine.
Dr. Albers is the director of the Stanford Stroke Center, a position he has held
since co-founding the center in 1992. Dr. Albers is an internationally recognized
scientist and clinician who has been a pioneer in the diagnosis, management, and
prevention of ischemic stroke. Dr. Albers and his team use advanced imaging
technology to expand the treatment window for ischemic stroke. He has been the
principal investigator of all 3 DEFUSE studies, which were NIH-funded research
projects that clarified the evolution of brain ischemia and led to extending the
treatment window for stroke to 24 hours in 2018. A prolific and distinguished
researcher, Dr. Albers has authored more than 450 articles on topics related to
cerebrovascular disease in peer-reviewed journals. Dr. Albers will be lecturing on
the revolution in the rapid diagnosis and treatment of ischemic stroke. Modern
imaging techniques that provide visualization of the ischemic core and penumbra
have made the stroke treatment window transparent, which allows therapy to be
tailored based on individual characteristics of specific patients. These advances
have led to unprecedented progress in the treatment of acute stroke. Based on
precision medicine techniques, in 2018 a quadrupling of the treatment window for
stroke therapy was extended from 6 to 24 hours for eligible patients.
Throughout the conference, parallel panel presentations and daily poster sessions
will span the breadth of neuroscience. Additional elements of the program warrant
your attention. There will be two career development sessions, the first on Sunday,
January 26th and the second on Tuesday, January 28th. In memorial to one of the
mainstays of WCBR, a special session will be held in honor of Conan Kornetsky
on Sunday, January 26th. On Wednesday evening, a special poster session will
showcase the highest ranked posters from junior investigators. Please note that the
Mountain Lunch will be Wednesday, January 29th. Skiers and non-skiers should
all join together at this festive gathering!
The conference is pleased to host our first Diversity and Inclusion Coffee Hour
on Monday, January 27th at 2:30 pm. Please join Kyle Frantz and other members
of the Board of Directors in this interactive event to promote participation in all
aspects of WCBR, from presentations to travel fellowships to board membership
for our increasingly diverse meeting attendees. Improving the diversity of our

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 1

attendees and leadership is a priority for WCBR as we move forward. As part
of WCBR’s commitment to diversity and fostering a welcoming and inclusive
environment, we are pleased to host a special session on the evening of Monday,
January 27th at 7:00 pm, “Improving the Climate in Scientific Disciplines”.
Two WCBR “Pioneer” panels will take place during the meeting, honoring the
work of some the most accomplished scientists who have been regular attendees
and leaders of WCBR over the past several decades. These sessions will each
feature one speaker who has regularly attended the conference for decades and
whose research has had major impact in neuroscience, followed by two more-junior
speakers from the same field. The 2020 Pioneers are Drs. Fritz Henn and Eliot
Gardner. Dr. Henn has had a long and distinguished career in neuropsychiatry,
and currently is a Professor at Cold Spring Harbor Laboratory as well as a
Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai. Dr.
Henn has done seminal research combining imaging, animal studies, and genetics
to understand the biological bases of depression and schizophrenia. Dr. Henn
has had an outstanding career in academia, chairing a department of psychiatry,
running a major international research center in Germany, and recently serving as
the Associate Laboratory Director for Life Sciences for 4 years at the Brookhaven
National Laboratory. Dr. Gardner is a Senior Investigator in the Molecular Targets
and Medications Discovery Branch, Neuropsychopharmacology Section of NIDA.
Dr. Gardner has been a leader in the study of addiction for several decades. He has
conducted internationally recognized research directed toward the development
of effective anti-addiction, anti-craving, anti-relapse medications. His work has
centered around basic brain mechanisms underlying drug addiction, craving, and
relapse, endocannabinoid brain mechanisms and addiction, dopamine D3 receptor
antagonists, slow-onset long-acting dopamine transport inhibitors and drugs
acting on the endocannabinoid brain system. Please join us in honoring these two
Pioneers in neuroscience and active participation in WCBR.
The conference will also host outreach events for the local community including
school visits and a “brain talk” town meeting open to the general public. This
year’s Brain Talk Town Hall will be a presentation from our plenary speaker Dr.
Greg Albers, who will be discussing stroke prevention, diagnosis, and management
for the lay public. The talk will be held on Monday, January 27th at 7:00pm.
An important aspect of WCBR is the abundant opportunity for networking, from
the opening reception on Saturday night through to the banquet on Thursday
evening. Big Sky has amazing skiing, along with multiple dining options, shopping,
and other off-slope entertainment. It has extensive slopes for all levels, and plenty
of activities for non-skiers. The West Gate to Yosemite National Park is within an
hour’s drive from Big Sky and offers an unparalleled experience of scenic beauty
and wildlife in the winter. We are certain you will enjoy it.
Thomas M. Hyde, Conference Chair
53rd Winter Conference on Brain Research
Big Sky Montana, January 25-30, 2020

2 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 Contents
General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Continuing Medical Education (CME). . . . . . . . . . . . . . 6
Committees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Travel Fellowship Program. . . . . . . . . . . . . . . . . . . . . . . . . .8
Conference Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Exhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Pioneer Awardees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Featured Presenter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Winter WCBR Policy Information . . . . . . . . . . . . . . . . . 16
Program. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Saturday, January 25, 2020. . . . . . . . . . . . . . . . . . . . . . 19
Sunday, January 26, 2020. . . . . . . . . . . . . . . . . . . . . . . 19
Monday, January 27, 2020. . . . . . . . . . . . . . . . . . . . . . 22
Tuesday, January 28, 2020 . . . . . . . . . . . . . . . . . . . . . . 24
Wednesday, January 29, 2020 . . . . . . . . . . . . . . . . . . . 27
Thursday, January 30, 2020 . . . . . . . . . . . . . . . . . . . . . 29
Poster Session I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Poster Session II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Poster Session III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Poster Session IV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Panel Session Abstracts. . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Poster Abstracts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Presenter Disclosures. . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 3

 General Information
WCBR INFORMATION DESK AND MESSAGE
CENTER are located at the Yellowstone Conference Center, Upper Atrium.

The Information Desk hours are as follows:

Saturday, January 25, 2020 12:00 p.m. – 7:00 p.m.
Sunday, January 26, 2020 7:00 a.m. – 7:30 p.m.
Monday, January 27, 2020 7:00 a.m. – 7:30 p.m.
Tuesday, January 28, 2020 7:00 a.m. – 7:30 p.m.
Wednesday, January 29, 2020 7:00 a.m. – 10:00 a.m.
& 3:00 p.m. – 6:00 p.m.
Thursday, January 30, 2020 7:00 a.m. – 6:00 p.m.

Pick up your badge at the WCBR Information Desk in the Yellowstone

Conference Center, Upper Atrium. Any additional items purchased (such
as guest meal tickets, printed program book, etc.) will also be available at
registration.
Exhibits and Poster Sessions are in Jefferson and Madison. Light refreshments
are provided from 3:30 p.m. – 4:30 p.m., Sunday, January 26th through
Wednesday, January 29th. Exhibitor setup is Sunday, January 26th, from 12:00
p.m. – 3:00 p.m. All exhibitors should have their materials removed by 10:00
p.m. on Wednesday, January 29th.
POSTER SESSION 1, SUNDAY, JANUARY 26th
Posters can be set up after 11:30 a.m. on Sunday.
Posters will be available for viewing from 12:00 p.m. – 7:00 p.m. on Sunday.
Presenters will be at their posters from 3:30 p.m. – 4:30 p.m. Posters must be
removed by 8:30 p.m. on Sunday.
POSTER SESSION 2, MONDAY, JANUARY 27th
Posters must be set up between 8:00 a.m. – 11:30 a.m. on Monday.
Posters will be available for viewing from 12:00 p.m. – 7:00 p.m. on Monday.
Presenters will be at their posters from 3:30 p.m. – 4:30 p.m. Posters must be
removed by 8:30 p.m. on Monday.

4 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

POSTER SESSION 3, TUESDAY, JANUARY 28th
Posters must be set up between 8:00 a.m. – 11:30 a.m. on Tuesday.
Posters will be available for viewing from 12:00 p.m. – 7:00 p.m. on Tuesday.
Presenters will be at their posters from 3:30 p.m. – 4:30 p.m. Posters must be
removed by 8:30 p.m. on Tuesday.
POSTER SESSION 4, WEDNESDAY, JANUARY 29th
Posters must be set up between 8:00 a.m. – 11:30 a.m. on Wednesday.
This is a special session displaying the highest-ranked posters by young
investigators. A grand prize and several other prizes will be presented to the best
posters. Presenters will be at their posters from 3:30 p.m. – 4:30 p.m. and return
for the special session from 7:30 p.m. – 9:30 p.m. Posters must be removed by
10:00 p.m. on Wednesday.
Please refer to pages 31–38 for a listing of poster sessions.
BREAKFAST is served to all conference delegates during the keynote
presentation on Sunday, January 26th from 7:00 a.m. – 8:30 a.m. in the Missouri
Ballroom. Tickets are not required for the Sunday breakfast.
Monday through Thursday breakfast will be available from 6:30 a.m. – 10:30
a.m., in Huntley Dining Room & Peaks Restaurant (Summit Hotel).

Don't forget to
visit the posters
& exhibits

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 5

 Continuing Medical
Education (CME)
SATISFACTORY COMPLETION
Learners must complete an evaluation form to receive a certificate of
completion. Your chosen sessions must be attended in their entirety. Partial
credit of individual sessions is not available. If you are seeking continuing
education credit for a specialty not listed below, it is your responsibility to
contact your licensing/certification board to determine course eligibility for
your licensing/certification requirement.

PHYSICIANS
In support of improving patient care, this activity has been planned and
implemented by Amedco LLC and the Winter Conference on Brain Research
(WCBR). Amedco LLC is jointly accredited by the Accreditation Council
for Continuing Medical Education (ACCME), the Accreditation Council for
Pharmacy Education (ACPE), and the American Nurses Credentialing Center
(ANCC), to provide continuing education for the healthcare team.
Credit Designation Statement – Amedco LLC designates this live activity
for a maximum of 30.5 AMA PRA Category 1 Credits™ for physicians.
Physicians should claim only the credit commensurate with the extent of their
participation in the activity.

6 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 Committees
BOARD OF FACILITIES CHAIRS
DIRECTORS
Isabelle Aubert, Chair
Isabelle Aubert David Devilbiss, Past Chair
Jill Becker
Lakshmi Devi PROGRAM CHAIRS
David Devilbiss AND COMMITTEE
Carrie Ferrario Peter Morgan, Chair
Kyle Frantz Lloyd Fricker, Past Chair
Lloyd Fricker Jill Becker
Amelia Gallitano William Birdsong
Tom Hyde Candice Contet
Brady Maher Sonsoles de Lacalle
Elyssa Margolis Arif Hamid
Jacqueline McGinty Kaiwen He
Peter Morgan Thomas Hyde
Milos Pekny Alfredo Kirkwood
Peter Ruben Brady Maher
Gretchen Snyder Marisela Morales
Sybil Stacpoole Daniel Morgan
Anurag Tandon Kyle Smith
Matthew Wanat Sybil Stacpoole
Catharine Winstanley Anurag Tandon
Elmer Yu Ryan Vandrey

CONFERENCE SMITTY STEVENS

CHAIRS RACE COORDINATOR
Thomas Hyde, Chair Isabelle Aubert
Kyle Frantz, Chair-Elect
TREASURER
EDUCATION CHAIRS Jacqueline McGinty
Gretchen Snyder, Chair
Lakshmi Devi, Chair-Elect

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 7

Travel Fellowship Program
FELLOWSHIP Sofia Lopez Stephanie Borgland
COMMITTEE Elizabeth Lucas Denise Cai
Gretchen Snyder, Chair Daniel Manvich Erin Calipari
Erik Carlson Bridget Erik Carlson
Lique Coolen Matikainen-Ankney Matt Carter
Karen Greif Philipp Mews Elena Chartoff
Edward Hall Jonathan Murphy Akiva Cohen
Kristen Harris Riley Perszyk Candice Contet
Tod Kippin Marc Pisansky Bradley Cooke
Joel Kleinman Anna Radke Laurence Coutellier
Victoria Luine David Root, Alain Dagher
Carl Lupica Conan Kornetsky Lakshmi Devi
recipient David Devilbiss
Anil Malhotra
Robert Rozeske Elva Diaz
Elyssa Margolis
Tayler Sheahan Kamran Diba
John Mendelson
Katharine Smith Lauren Ellman
Gretchen Neigh
Michael Stefanik Carrie Ferrario
George Wilcox
Casey Vickstrom Michael Frank
2020 Andrew Westbrook Richard Frye
FELLOWSHIP Jenny Wilkerson Amelia Gallitano
AWARDEES Samantha Yohn Eliot Gardner
Amber Alhadeff Moriel Zelikowsky, Dan Geschwind
Noelle Anastasio Ann Kelley recipient Mark Geyer
Eden Anderson Christopher Sam Golden
Lillian Brady Zimmerman Nigel Greig
Rianne Campbell Natalie Zlebnik Josee Guindon
Maria Diehl
FELLOWSHIP Carolina Haass-Koffler
Ewa Galaj MENTORS J. Marie Hardwick
William Giardino Kristen Harris
Isabelle Aubert
Erica Grodin Eric Harris
Jaideep Bains
Nick Hollon Matthew Hearing
Debra Bangasser
Jennifer Honeycutt Gregg Homanics
Jessica Barson
Jonna Jackson Jon Indik
Helen Bateup
Amy Johnson Morgan James
Jill Becker
Dean Kirson Joshua Johansen
Jennifer Bizon
Munir Kutlu Elizabeth Jonas
Julie Blendy
Alberto Lopez Leonard Kaczmarek

8 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Marsida Kallupi John Mendelson Jason Shepherd
Anushree Karkhanis Marisela Morales Cody Siciliano
Jibran Khokhar Jonathan Morrow Kyle Smith
Anna Klintsova Leslie Morrow Leslie Sombers
Lori Knackstedt Katherine Nautiyal Michael Tamkun
James Knowles Christopher Olsen Anurag Tandon
Julia Lemos Kathie Olsen Bradley Tanner
Michael Levine Caitlin Orsini Jeffrey Tasker
Aron Lichtman James Otis Lin Tian
David Lovinger Martin Paukert Stephen Traynelis
Hui-Chen Lu Paul Phillips Alexa Veenema
Victoria Luine Mikhail Pletnikov Marco Venniro
Rajtarun Madangopal Jason Radley Kate Wassum
Elyssa Margolis Lara Ray Anne West
Robert McCullumsmith Darleen Sandoval Leslie Whitaker
Zoe McElligott Marek Schwendt Catharine Winstanley
Jacqueline McGinty Annabell Segarra Long-Jun Wu
Lance McMahon Melissa Sharpe Zhenyu Yue

Don't forget to
visit the posters
& exhibits

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 9

 Conference Support
EDUCATIONAL GRANTS
The Winter Conference on Brain Research and Amedco would like to
acknowledge the generosity of the companies and institutions listed below
whose unrestricted educational grants have contributed to the overall quality of
this meeting.
Supernus Pharmaceuticals
The National Institute on Drug Abuse and the National Institute
on Alcohol and Alcoholism of the National Institutes of Health
under Award Number R13 DA047792.
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of Health.

CORPORATE SPONSORS
The Winter Conference on Brain Research appreciates the generous
contribution of our Corporate Supporters.

INDIVIDUAL SPONSORS AND

ORGANIZATIONS
Thank you to the individuals and organizations that generously support the
Travel Fellowship Program. The gift you make is used exclusively to introduce
young neuroscientists to the WCBR meeting.

Gold Sponsors ($100 and above) Silver Sponsors (up to $99)

Thomas Bleck Gaylen Edwards
Lloyd Fricker Iris Lindberg
Karen Greif Jeffrey Tasker
Michael Hoppa Claude Wasterlain
Michael Levine
Gretchen Snyder

10 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 Exhibitors
ANTIBODIES INC PHOSPHOSOLUTIONS
P.O. Box 1560 12635 E. Montview Blvd. #213
Davis, CA 95617-1560 Aurora, CO 80045
Contact: Will Fry Contact: Kameron Simpson
Tel: 530-758-4400; Tel: 720-859-4050
530-574-1848 (cell) sim@[Link]
wfry@[Link]

STOELTING
AVES LABS 620 Wheat Lane
P.O. Box 1560 Wood Dale, IL 60191
Davis, CA 95617-1560 Contact: Trent Lund
Contact: Jean Teh Tel: 800-860-9700
Tel: 530-758-4400 info@[Link]
jeanteh@[Link]

Unstaffed Table
ISCHEMAVIEW
Redwood City, California MARY ANN LIEBERT,
Contact: Kim DeGallier, INC. PUBLISHERS
Associate Territory Manager - 140 Huguenot Street
West– 425-736-2174 3rd Floor
RAPID AI. 650-388-9767 ext 2 New Rochelle, NY 10801-5215
Support@[Link] Contact: Sara McCarthy
kimdegallier@[Link] Tel: 914-740-2180
SMcCarthy@[Link]

MBF BIOSCIENCE
185 Allen Brook Lane
Suite 101
Williston, VT 05495
Contact: Susan Tappan
Tel: 802-288-9290
susan@[Link]

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 11

 Pioneer Awardees
For the 53rd WCBR meeting, we are honoring two scientists who have
greatly contributed to the field of neuroscience, as well as to WCBR. These
Pioneers will present their work during the special Pioneer Sessions on
Sunday, January 26th and Tuesday, January 28th.

ELIOT L. GARDNER, PH.D.

Dr. Eliot L. Gardner was born and raised
in Boston, and learned to ski at age 7
on local hills (wooden skis, bear-trap
bindings, real old-school). Originally a
mathematics major at Harvard College,
he enrolled in a psychopharmacology
course at Harvard Medical School in his
junior year, and was captivated by the
subject. He spent his last two years at
Harvard learning psychopharmacology
in depth – as a research assistant
in the Psychopharmacology Research Unit, and making morning
psychopharmacology rounds of patients with the senior members of the
Unit. After receiving his A.B. from Harvard in 1962, he moved to Montreal
to further his studies in psychopharmacology and neuroscience at McGill
University, the Queen Elizabeth Hospital, the Royal Victoria Hospital,
and the Montreal Neurological Institute. He received an M.A. degree
from McGill in 1964, and a Ph.D. in 1966. From 1966 to 1969, he served
as a medical research officer (Captain, Biomedical Sciences Corps) in the
U.S. Air Force – serving as a branch chief at the U.S. Air Force School of
Aerospace Medicine’s enormous non-human primate research center at
Alamogordo (White Sands), New Mexico. In 1969, he embarked upon a
2-year postdoctoral fellowship in pharmacology, followed by a second 2-year
postdoctoral fellowship in neurology, at Albert Einstein College of Medicine
in New York City. He was then offered a junior faculty appointment
at Albert Einstein, and remained on faculty there for 33 years – in the
Departments of Pharmacology, Neurology, Psychiatry, and Neuroscience.
In 2000, he was recruited to the Intramural (in-house) Research Program
at the National Institute on Drug Abuse of NIH, where he is Chief of
the Neuropsychopharmacology Section in the Molecular Targets and
Medications Discovery Research Branch.
Eliot has devoted his research career to studying brain reward mechanisms
and the neurobiology of addiction. He was one of the first to propose that

12 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

dopamine is the essential neurotransmitter of the brain’s principal reward
pathway from ventral tegmental area to nucleus accumbens. He was also
the first to show that delta-9-tetrahydrocannabinol activates brain reward
mechanisms – deriving its addictive potential therefrom. And that highly
selective cannabinoid CB1 antagonists and CB2 agonists have potent anti-
addiction potential. He was also the first to show that highly selective dopamine
D3 receptor antagonists have potent anti-addiction efficacy against a remarkably
wide range of addictive substances in a remarkably wide range of preclinical
animal models with arguably high translational relevance.
Eliot has received numerous awards and honors for his work – including the
Newton Society Prize, Fellow of the American Psychological Association,
Career Scientist Award of the Health Research Council of New York,
Distinguished Basic Science Scholar for the Year 2000 by the American
Academy of Addiction Psychiatry, and the NIH Director’s Merit and Honor
Awards.
Eliot has attended WCBR for more than 50 years – from its inception at the first
1968 meeting at Lake Tahoe. He has organized and participated in panels and
workshops, and competed in the Smitty Stevens race (never matching Chuck
O’Brien’s times, an unfulfilled – and unrealistic – long-time desire). He has also
participated in WCBR’s local school outreach program, and in Brain Talk Town
Meetings. When George Koob’s son Cameron was 4 years old, Eliot put the
young lad on skis for the first time at a WCBR meeting. Cameron now leaves
George, Eliot, and virtually everyone else in his dust on the slopes. Eliot has
exceptionally fond memories of skiing with Chuck O’Brien, Conan Kornetsky,
Tom Crowley, Roy Wise, Dave Kline, Kyle Frantz, Bert Weiss, Fritz Henn, Jim
McElligott, Bart Hoebel, and far too many others to mention. He treasures
the friendships, networking, and research collaborations formed on the slopes
and in the scientific sessions. He has also brought his students and postdocs to
WCBR meetings, helping to foster new generations of attendees.

FRITZ HENN, M.D., PH.D.

Dr. Fritz Henn is a psychiatrist and neuroscientist and
received his BA from Wesleyan University in1963, a
PH.D. in biochemistry from Johns Hopkins University
in 1967 and an MD from the University of Virginia
in 1971. His postdoctoral training was at Washington
University in Psychiatry and in Goteborg Sweden in
neurobiology. His initial faculty appointment was at
the University of Iowa in Psychiatry and he left as a full
Professor to assume the chair in Psychiatry and Director of the Long Island
Research Institute in 1980. He began attending WCBR while in Iowa and one

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 13

of his first experiences was to take some beautiful wooden cross country ski’s to
his first meeting at Keystone in the 70’s and go with some experts from British
Columbia to ski above Leadville where he developed mild pulmonary edema,
they got him off the mountain and there was an uneventful recovery. After
assuming the Chair at Stony Brook, Harvey Karten got him not only to attend
regularly but to become involved on the board and at the 25th anniversary of
the meeting he was President and led us to wet Whistler. Following Jill Becker
down a trail at Whistler I ended up falling into a 6 ft tree hole which took work
to get out of, I’m not sure she noticed. I really learned to ski at WCBR over
the years often with Conan giving me tips. In 1977 as president I worked with
Bill Greenough to move the meeting organization from the group which had
founded the meeting at UCLA into a University affiliated meeting with the U. of
Illinois. This was a difficult transition but appears to have been the right one for
WCBR.
Dr. Henn’s work beginning in Iowa was centered understanding depression and
on defining to role of astrocytes. An early PNAS paper was the basis for the idea
of a tripartite synapse, with astrocytes playing a role in glutamate transmitter
uptake and recycling back to neurons. Following this work he focused on
understanding depression using the animal model learned helplessness. In 1994
he made the decision to leave Stony Brook and accepted the Directorship of
the Central Institute of Mental Health (ZI) and a Professorship at Heidelberg
Germany. ZI became the leading psychiatric research center in Germany and
initiated the first substance abuse program in a University, under much protest.
Here both Chuck Obrien and Nora Volkow were invaluable. The work on
learned helplessness progressed with the development of inbred helpless and
non helpless lines. This lead to a new circuit being proposed for depression
involving the l. habenula. This work was done after his return to the United
States at Brookhaven National Lab and later at Cold Spring Harbor Lab. The
circuit has been tested in cases of intractable depression and although the DBS
target is a very difficult target patients who failed all treatment including ECT
have responded. Dr. Henn is a member of the German Academy of Science
and received the Distinguished Service Cross of Germany upon his retirement
there. He is a fellow of the AAAS in neuroscience and was a Professor at CSHL
and Mt. Sinai until his retirement from lab work 2 years ago. The clinical studies
of DBS are ongoing at Baylor with Dr. Gooden.

14 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 Featured Presenter
GREGORY ALBERS, M.D.
Gregory Albers, M.D., Director of the Stanford
Stroke Center, will be the 2020 Keynote and
Brain Talk Town Hall presenter. Dr. Albers’
research focus is the acute treatment and
prevention of cerebrovascular disorders. He
and his group’s primary interest is the use
of advanced imaging techniques to expand
the treatment window for ischemic stroke.
They are also conducting clinical studies
of both neuroprotective and thrombolytic
strategies for the treatment of acute stroke and
investigating new antithrombotic strategies for
stroke prevention.

KEYNOTE
Sunday, January 26, 2020 from 8:30 a.m. – 9:30 a.m.
How the Stroke Stopwatch was Shattered
Missouri Ballroom

BRAIN TALK TOWN HALL

Monday, January 27, 2020 from 7:00 p.m. – 8:30 p.m.
The Transparent Time Window: A New Perspective on Stroke Treatment
Talus Room

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 15

 Winter Conference on Brain
Research Policy Information
CODE OF CONDUCT
1. Introduction
The Winter Conference on Brain Research (WCBR) is dedicated to providing a safe,
productive and discrimination-free experience for all participants during the Annual
Meeting regardless of race, color, national origin, religion, creed, age, sex (including
pregnancy), gender, gender identity, physical or mental disability, perceived disability,
ancestry, marital status, genetic information, sexual orientation, citizenship, past, current
or prospective service in the uniformed services, or any other basis protected by federal,
state or local laws. WCBR does not tolerate discrimination or any form of harassment
and is committed to enforcing this Code of Conduct Policy. As a professional society,
the WCBR is committed to providing an atmosphere that encourages the free expression
and exchange of scientific and educational ideas. Furthermore, WCBR upholds the
philosophy of equality of opportunity for, and treatment of, all meeting participants,
including but not limited to, attendees, guests, speakers, exhibitors, contractors, staff,
and volunteers at all venues and events, including all ancillary and unofficial social
events held in conjunction with the Annual Meeting (collectively “Annual Meeting”).
2. Scope of Code of Conduct
WCBR seeks to create a diverse, inclusive and respectful environment for the exchange
of scientific information.
WCBR requires compliance with this Policy by all meeting participants throughout
the period of the Annual Meeting, whether in public or private facilities. This policy is
an expression of WCBR’s values and commitment to a safe and productive experience
for all participants at the Annual Meeting. This policy is not an acknowledgement,
admission, or description of WCBR’s legal obligations with respect to any of the subject
matters addressed herein, nor does it create any such legal obligations on WCBR, its
Board Members, and committee members.
3. Prohibited Conduct
Prohibited conduct at the WCBR Annual Meetings include, but is not limited to:
a. harassment and discrimination based on race, color, national origin, religion,
creed, age, sex (including pregnancy), gender, gender identity, physical
or mental disability, perceived disability, ancestry, marital status, genetic
information, sexual orientation, citizenship, past, current or prospective
service in the uniformed services, or any other basis protected by federal, state
or local laws;
b. demeaning comments or harassment about a person’s professional status,
qualifications, or affiliations;

16 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 c. sexual harassment, as defined in Section 4;
d. abusive conduct that has the purpose or effect of unreasonably interfering
with another person’s ability to benefit from and enjoy or participate in the
Annual Meeting;
e. undue or excessive interruption of any event, speaker, or session; and
f. violence or threats of violence or physical harm.
4. Harassment Defined
Prohibited harassment includes any conduct that creates an intimidating, offensive, or
hostile environment whether that conduct be verbal, physical, or visual. Harassment
can take many forms and includes, but is not limited to, the following: slurs, epithets,
derogatory comments, insults, degrading or obscene words, jokes, demeaning
statements, offensive gestures, or displaying derogatory or demeaning pictures, photos,
drawings, or cartoons based upon an individual’s race, color, national origin, religion,
creed, age, sex, pregnancy, gender, gender identity, physical or mental disability,
perceived disability, ancestry, marital status, genetic information, sexual orientation,
citizenship, past, current or prospective service in the uniformed services, or any other
basis protected by federal, state or local laws. Sexual harassment includes unwanted
sexual attention including expressions of romantic or sexual interest that are unwelcome,
unreciprocated, and/or offensive to the target; examples include unwanted touching,
hugging, stroking, and persistent requests for dates or sexual behavior despite
discouragement. Sexual harassment also includes gender harassment which includes
verbal and nonverbal behaviors that convey insulting, hostile, and degrading attitudes
about members of one gender as well as crude harassment.
Sexually harassing conduct can be by a person of either the same or other sex. Conduct
that begins as consensual in nature may become harassment if one party withdraws his
or her consent. Sexual or other harassment prohibited by this policy is unacceptable and
will not be tolerated.
The above list of prohibited behaviors is not a complete rendering of what may be
deemed sexual or other harassment prohibited by this policy. It is impossible to define
every action or word that could be interpreted as harassment or discrimination.
However, WCBR has a “zero tolerance” policy toward discrimination and all forms of
harassment. WCBR reserves the right to discipline meeting participants who engage in
any inappropriate conduct, even if it is not specifically referred to or defined in this Code
of Conduct, or is not legally actionable as sexual or any other form of harassment.
5. Filing a Formal Complaint
If you feel you have been subject to or have witnessed a violation of this Code of
Conduct, a formal complaint can be filed with an authorized representative from our
meeting management company, Parthenon Management Group, LLC. This individual
can be contacted through the registration desk, or if after the Annual Meeting, at
615-324-2365. No participant will be retaliated against for making a good faith claim
of harassment or discrimination, for opposing harassment or discrimination, or for
participating in, or cooperating with, the investigation of a complaint. A designated
member of the Parthenon team will gather information and put together a summary

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 17

report, which will then be forwarded to the Conduct Subcommittee of the Executive
Board of WCBR for a decision. If the decision of the Subcommittee is contested, it can
be appealed to the full Executive Board. The decision following appeal is final and not
subject to further appeal. We will strive to keep the identity of the complainant and
any witnesses, as well as the accused individual, confidential throughout this process.
All participants of the Annual Meeting are bound by the decisions of the Conduct
Subcommittee of the Executive Board. If it is determined that an individual has engaged
in conduct constituting harassment or discrimination, discipline may be imposed, up to
and including exclusion from participating in the WCBR Annual Meeting, and/or future
meetings.
Code of Conduct Attestation:
The WCBR Annual Meeting is committed to supporting discovery and scientific
dialogue, and providing an atmosphere that is safe, respectful and welcoming to all
those present in order to encourage the free expression and exchange of scientific and
educational ideas. This commitment applies to the WCBR Annual Meeting, at all venues
and events, including all ancillary and unofficial social events held in conjunction with
the Annual Meeting (collectively “Annual Meeting”) and anyone present, including but
not limited to, attendees, guests, speakers, exhibitors, contractors, staff, and volunteers.
To that end, the WCBR Annual Meeting strictly prohibits and does not tolerate
unlawful harassment or discrimination on the basis of race, color, religion, creed,
national origin, ancestry, sex (including pregnancy), sexual orientation, gender
(including nonconformity and status as a transgender or transsexual individual), gender
identity, age, physical or mental disability, perceived disability, citizenship, marital status,
genetic information, past, current or prospective service in the uniformed services, or
any other basis recognized by applicable federal, state, or local laws. WCBR upholds the
philosophy of equality of opportunity for, and treatment of, all individuals present at
the Annual Meeting and thus, does not tolerate any form of discrimination, harassment,
and/or retaliation. We expect all those present at the Annual Meeting of the WCBR to
help us in ensuring a productive, safe and positive environment for all.
By registering for the meeting, I confirm that I have read the Code of Conduct for the
WCBR, and agree that it is my responsibility to be familiar with, and to abide by, its
terms. I also attest that I will cooperate with any formal or informal inquiry into my
behavior and/or actions at the Annual Meeting. I agree to be bound by the decisions
of the Executive Subcommittee on Meeting Conduct, which may take any action that
it deems appropriate, including but not limited to exclusion from a current Annual
Meeting (without refund) or from future meeting.

PHOTOGRAPHY AND VIDEOGRAPHY POLICY

WCBR does not allow photography or videography of oral presentations, slides and/or
posters without permission from the presenter. At the beginning of the presentation, the
presenter must either grant permission to the audience and/or include an icon on the
first slide or poster signifying photos or videos are allowed.

18 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

 Program
SATURDAY, JANUARY 25, 2020
6:00 P.M. - 6:30 P.M. 6:30 P.M. - 7:30 P.M.
Welcome Reception for Newcomers, Welcome Reception (All are
Travel Fellows, and Mentors • welcome!) • Jefferson/Madison
Huntley Dining Room

SUNDAY, JANUARY 26, 2020

7:00 A.M. - 8:30 A.M. 2:00 P.M. - 3:30 P.M.
Breakfast • Missouri Ballroom Career Development Session # 1 •
Cheyenne
8:30 A.M. - 9:30 A.M. NIH Grant Application & Reviews
Plenary • Missouri Ballroom Brad Cooke (Chair), David Devilbiss,
How the Stroke Stopwatch was Lakshmi Devi, Gretchen Snyder, Paul
Shattered Phillips, Dana Plude
Gregory Albers
3:30 P.M. - 4:30 P.M.
9:45 A.M. - 11:00 A.M. Exhibits & Poster Session I • Jefferson/
Pioneer Session # 1: Fritz Henn • Madison
Amphitheater
4:30 P.M. - 6:30 P.M.
Understanding the Neurobiological
Basis of Depression Panel • Amphitheater
Pioneer: Fritz Henn Contribution of Glia to Brain Function
Chair: Lloyd Fricker and Disorders
Investigators: Bo Li, Alexander Yongjie Yang, Martin Paukert
Sartorius (Co-Chair), Long-Jun Wu, Hye Young
Lee (Chair)
12:30 P.M. - 2:00 P.M. Panel • Canyon
Special Session • Dunraven/Obsidian Neuroendocrine and Neuroimmune
Conan Kornetsky’s Memorial Panel Modulation in Stress and
Jacqueline McGinty (Chair), George Addiction
Koob, Linda Porrino, Chris Pierce, Dean Kirson (Co-Chair), Zoe
David Root McElligott, Kelly Cosgrove, Carolina
Haass-Koffler (Chair)
JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 19
SUNDAY, JANUARY 26, CONTINUED
Panel • Cheyenne 6:30 P.M. - 7:00 P.M.
Kratom –Potential Drug of Abuse or Refreshment Break • Upper Atrium
Useful Analgesic Without Opioid-
Like Side-Effects? 7:00 P.M. - 8:30 P.M.
Daniel Morgan (Chair), Christopher Panel • Amphitheater
McCurdy, Abhisheak Sharma,
Pain and Itch: How are They
Lance McMahon, Jenny Wilkerson
Motivating You?
(Co-Chair)
Paul Phillips (Chair), Tamara
Panel • Dunraven/Obsidian
Markovic, Amber Alhadeff, Tayler
Frontal Cortical Regulation of Sheahan
Motivated Behaviors
Panel • Canyon
Evan Hart, Cody Siciliano (Co-Chair),
Viral Vectors for Gene Modifications
Christina Gremel, Vijay Mohan K.
to Enable Axon Regeneration
Namboodiri (Chair)
Kevin Park, Binhai Zheng, Oswald
Panel • Gallatin
Steward (Chair)
Neural Systems Mediating Passive and
Panel • Cheyenne
Active Responses During Aversive
Situations It’s Not All Dopamine: The Role of
Serotonin in the Regulation of
Lindsay Halladay, Mahsa Moaddab,
Impulsive Behavior
Maria Diehl, Matthew Wanat (Chair)
Catharine Winstanley, Noelle
Panel • Gibbon
Anastasio, Katherine Nautiyal (Chair)
New Treatment Strategies for Mood
Panel • Dunraven/Obsidian
Disorders: From IBT to ECT
Long-Term Behavioral and
Anna Van Meter, Anil Malhotra
Neurobiological Effects of
(Chair), Daphne Voineskos, Miklos
Adolescent Drug Use
Argyelan
Elizabeth Pitts (Chair), Anushree
Panel • Lake
Karkhanis, Mary Torregrossa
Synaptic Transmission and Plasticity
Panel • Gallatin
Regulated by Neurotransmitter
Receptor Auxiliary Subunits Cholinergic Modulation Shapes
Striatal Microcircuitry: Roles
Yael Stern-Bach, Andres Maricq, David
in Reinforcement Learning and
Bredt (Chair), Wei Lu
Reward-Seeking Behavior
Panel • Lamar
David Lovinger, Kate Wassum,
New Approaches to Treating Patients Samantha Yohn (Chair), Mark Ferris
in Status Epilepticus
Thomas Bleck, Hilary McCarren,
Claude Wasterlain, Denson Fujikawa
(Chair)

20 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Panel • Gibbon Panel • Lamar
Investigating Brain Circuits Visual Circuit Function and Plasticity
in Neurodevelopmental Huizhong Tao (Chair), Jianhua Cang,
Disability, From Molecular to Nicholas Priebe, Sandra Kuhlman,
Electrophysiological Aspects Hey-Kyoung Lee
Francois Bolduc (Chair), Sarah Lippe,
Jean-Francois Lepage
Panel • Lake
Obesity Induced Changes to Brain
Motivation Circuits
Richard O’Connor (Chair), Bridget
Matikainen-Ankney, Morgan James

Save the Date!

Winter Conference
on Brain Research
JANUARY 23-28, 2021
SNOWBIRD, UTAH

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 21

MONDAY, JANUARY 27, 2020
6:30 A.M. - 8:30 A.M. Panel • Gallatin
Board of Directors Meeting Molecular Adaptations Underlying
(Invitation Only) • Talus Motivation and Drug-Associated
Behaviors
6:30 A.M. - 8:30 A.M. Alberto Lopez (Chair), Megan
Breakfast at Leisure • Huntley Dining Fox, Rianne Campbell (Co-Chair),
Room/Peaks Restaurant Courtney Miller
Panel • Gibbon
7:30 A.M. - 9:30 A.M. Circuits and Functions of Neurons
Panel • Amphitheater Defined by Multiple Genetic
Sex Differences in the Effects of Characteristics
Cannabis and Cannabinoid Marisela Morales (Co-Chair), Lief
Signaling Fenno, Susana Mingote, Patricia
Aimee McRae-Clark, Elise Weerts, Jensen, David Root (Chair)
Ryan McLaughlin (Chair), Matthew Panel • Lake
Hill Rhythms on the Slope
Panel • Canyon Kamran Diba (Chair), Lara Rangel,
Advancements in Psychedelic Amy Griffin, Andrew Maurer
Neuroscience (Co-Chair), Carmen Varela
David Martin (Chair), Natalie Panel • Lamar
Hesselgrave, Cristopher Niell, Katrin Neuropeptide Signaling Mechanisms:
Preller From Molecules to Circuits to
Panel • Cheyenne Behavior
Fatal Fentanyl: How One Pill Can Kill Jenny He, Julia Lemos (Co-Chair),
Terrence Boos, Irma Cisneros Alexa Veenema, William Giardino
(Co-Chair), Kim Janda, Phil Skolnick (Chair)
(Chair)
2:30 P.M. - 3:30 P.M.
Panel • Dunraven/Obsidian
Diversity and Inclusion Coffee Hour •
From Clusters to Stroke Busters:
Dunraven/Obsidian
The Cellular, Molecular and
Translational Biology of Kv2.1/ 3:30 P.M. - 4:30 P.M.
Neuregulin Complexes
Exhibits & Poster Session II •
Elias Aizenman (Chair), Michael
Jefferson/Madison
Tamkun, Andres Buonanno, Robert
Fyffe, Anthony Schulien

22 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

4:30 P.M. - 6:30 P.M. Panel • Lake
Panel • Amphitheater New Developments on Hypothalamic
and Brainstem Control of
Genetic In Vivo Models of
Defensive Behaviors
Neurological Disease
Sung Han, Jaideep Bains, Jason Radley,
Wayne Frankel, Stephen Traynelis
Avishek Adhikari (Chair)
(Chair), Geoffrey Swanson, Jennifer
Kearney Panel • Lamar
Panel • Canyon Structural, Functional and Molecular
Mechanisms of Dendritic Spine
Striatal Interneurons: Orchestrating
Plasticity
Synaptic and Behavioral
Adaptations Yi Zuo (Chair), Kristen Harris, Ryohei
Yasuda, Jason Shepherd
Patrick Rothwell, Anne West, Brad
Grueter (Chair), Brian Mathur
7:00 P.M. - 8:30 P.M.
Panel • Cheyenne
Special Session • Amphitheater
Cannabinoids, Sleep and PTSD: A
Improving the Climate in Scientific
Bench to Clinic Primer
Disciplines
Andrew Kesner, Margaret Haney, Ryan
Jill Becker (Chair), Kathryn Clancy,
Vandrey (Chair), Marcel Bonn-Miller
Paul Phillips, Jonathan Morrow, Carrie
Short Course • Dunraven/Obsidian Ferrario
Analysis, Visualization and Data Brain Talk Town Meeting • Gallatin
Sharing for Human Intracranial
The Transparent Time Window:
Recording and Stimulation
A New Perspective on Stroke
Michael Beauchamp (Chair), Kai Treatment
Miller, Dora Hermes, Dominique
Gregory Albers
Duncan, John Magnotti,
Panel • Gallatin 9:00 P.M. - 11:00 P.M.
It’s all Downhill From Here:
Karaoke • Montana Jack
Dopamine Function and
Dysfunction in Movement
Initiation
Elyssa Margolis (Chair), Jakob Dreyer,
Mark Howe, Alexandra Nelson, Leslie
Sombers (Co-Chair)
Panel • Gibbon
Linking Endocytosis to Neuronal
Survival
J. Marie Hardwick, Leonard
Kaczmarek, Elizabeth Jonas (Chair),
Zhenyu Yue

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 23

TUESDAY, JANUARY 28, 2020
6:30 A.M. - 8:30 A.M. Panel • Gallatin
Travel Fellow/Mentor Breakfast • Sex Differences in Opioid Use and
Chet’s Outcomes: From Synapses to
Circuits
6:30 A.M. - 8:30 A.M. Matthew Hearing (Chair), Anne
Breakfast at Leisure • Huntley Dining Murphy, Beverly Reyes, Suman Guha,
Room/Peaks Restaurant Eden Anderson (Co-Chair)
Panel • Gibbon
7:30 A.M. - 9:30 A.M. Crossed Wires and Dissolving Priors:
Panel • Amphitheater State-Dependent Changes in
Broadening the Neural and Associative Connectivity Within the Cortico-
Mechanisms of Fear Thalamic Network

Joshua Johansen, Melissa Sharpe Matthew Banks (Chair), Katrin

(Chair), Stephen Maren, Moriel Preller, Anthony Hudetz, Stefanie
Zelikowsky Blain-Moraes

Panel • Canyon Panel • Lake

Gene and Protein Networks in Autism Stability and Plasticity in

and Schizophrenia Hippocampal and Cortical
Networks
James Knowles, Dan Geschwind
(Co-Chair), Stephen Smith (Chair), Sebastien Royer, Gideon Rothschild,
Lilia Iakoucheva Kamran Diba (Chair), Andrew
Maurer
Panel • Cheyenne
Panel • Lamar
Neurobiological Mechanisms
Underlying the Potential Glutamate Receptors: From Structure
Therapeutic Effects of to Function
Psychedelics R. Suzanne Zukin (Co-Chair), Sabine
Melissa Herman (Chair), Mark Geyer, Spijker, August Smit, Johannes Hell
Samuel Slocum, William Wetsel, (Chair)
Harriet de Wit Panel • Talus
Workshop • Dunraven/Obsidian Heterogeneity of Midbrain VTA/
Educating the Next Generation: SNc Cells and the Properties
Innovative Approaches to Make Underlying Diversity of
Science Fun Neurotransmission

Lloyd Fricker (Chair), Sybil Stacpoole Chris Ford (Chair), Sarah Zych, Vivien
(Co-Chair), Ronald Harris-Warrick, Zell, Jorge Miranda-Barrientos, Louis-
Matt Carter, Karen Greif, Bradley Eric Trudeau
Tanner

24 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

9:45 A.M. - 11:00 A.M. Panel • Cheyenne
Pioneer Session # 2: Eliot Gardner • New Advances in Understanding of
Amphitheater Orexin/Hypocretin in Addiction:
Converging Evidence From
More Than 50 Years at WCBR – Brain
Physiological and Behavioral
Reward, Dopamine, the D3
Models in Multiple Species
Receptor, Atypical Dopamine
Transport Inhibitors, and Brooke Schmeichel, William Giardino
Cannabinoids (Co-Chair), Morgan James (Chair),
Sarah Leibowitz
Pioneer: Eliot Gardner
Chair: Amy Newman Panel • Dunraven/Obsidian
Investigators: Andrea Hohmann, Obesity and the Regulation of Body
Zheng-Xiong Xi Weight – It’s Not All in Your Head
Carrie Ferrario (Chair), Kevin
2:00 P.M. - 3:30 P.M. Williams, Lloyd Fricker (Co-Chair),
Career Development Session # 2 • Darleen Sandoval, Ian Willis
Cheyenne Short Course • Gallatin
Tips and Tools for Success in New and Evolving Imaging
Academia Approaches for Evaluating Neural
Lakshmi Devi (Chair), Kyle Frantz, Circuit Activity
Stephanie Borgland, Lloyd Fricker Megha Sehgal, Jonathan Marvin, Vijay
Mohan K. Namboodiri, James Otis
3:30 P.M. - 4:30 P.M. (Chair)
Exhibits & Poster Session III • Panel • Gibbon
Jefferson/Madison Of Shape and Function: Microtubule
Remodeling in Neurological and
4:30 P.M. - 6:30 P.M. Psychiatric Disorders
Panel • Amphitheater Annie Andrieux, Eleanor Coffey,
The Highs and Lows of GABAergic Amynah Pradhan (Co-Chair),
Transmission in Anxiety: Candice Contet (Chair)
Reconciling Contradictory Panel • Lake
Findings From Rodents and
A Better Pair of Goggles: Super-
Humans Studies
Resolution Imaging of Synapses
Elif Engin, Elizabeth Lucas, Laurence
Daniel Choquet, Matthew Dalva,
Coutellier (Chair), Georg Oeltzschner
Katharine Smith, Mark Dell’Acqua
Panel • Canyon (Chair)
Recent Insights Into the Panel • Lamar
Neurobiological Mechanisms
Why Can’t You Hear Me? “Auditory”
Underlying Opioid Self-
Circuits in Health and Disease
Administration and Reinstatement
Patrick Kanold (Chair), Li Zhang
Marsida Kallupi, Heath Schmidt,
(Co-Chair), Merri Rosen, Jan Schnupp,
Jennifer Fragale, David Reiner (Chair)
Shaowen Bao, Gregg Recanzone

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 25

TUESDAY, JANUARY 28, CONTINUED
Panel • Talus Panel • Gallatin
Dopaminergic Modulation of Ventral Striatum Dopamine Encoding
Learning and Cognition of Learning and Motivated
Amy Johnson (Co-Chair), Munir Kutlu Behaviors
(Chair), Daniel Covey, Stephanie Matthew Wanat, Ryan Farero (Chair),
Borgland, Joshua Berke Erin Calipari
Panel • Gibbon
6:30 P.M. - 7:00 P.M.
Regulation of Motivation for Food,
Refreshment Break • Upper Atrium Sex and Drugs by Ovarian
Hormones
7:00 P.M. - 8:30 P.M.
Tracy Fetterly, Jill Becker, Annabell
Panel • Amphitheater Segarra, Yanaira Alonso-Caraballo
Reacting to the Bumps: Diverse (Chair)
Mechanisms Through Which Panel • Lake
Different Systems Maintain Epileptology: From Basic Science to
Homeostasis Applied Bioengineering
Shane Hentges (Chair), Zachary Olaf Paulson (Chair), Claude
Knight, Matt Carter, Stephanie Padilla, Wasterlain, Lars H. Pinborg, Sándor
Andrew Rau Beniczky
Panel • Canyon Panel • Lamar
Computational Models of Inhibitory Autism Spectrum Disorder:
Control Mechanisms and Potential
Alain Dagher (Chair), Michael Frank, Treatments
Valerie Voon, Frederike Petzschner Brigitta Gundersen (Co-Chair), Hui-
Panel • Cheyenne Chen Lu, Hsiao-Huei Chen (Chair),
Candidate Neuroimaging Biomarkers Evdokia Anagnostou
for Synucleinopathies
Xiaoping P. Hu (Co-Chair), Daniel
Huddleston (Chair), Kejal Kantarci
Workshop • Dunraven/Obsidian
Life Science Entrepreneurship:
Should You Take the Slope That
Leads to Commercialization?
Bradley Tanner (Chair), Jason Eriksen,
Susan Tappan

26 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

WEDNESDAY, JANUARY 29, 2020
6:30 A.M. - 8:30 A.M. Panel • Gallatin
Breakfast at Leisure • Huntley Dining The Spectrum of Social Behavior and
Room/Peaks Restaurant its Underlying Mechanisms
Marco Venniro (Chair), Marijke
7:30 A.M. - 9:30 A.M. Achterberg, Alexa Veenema, Sam
Panel • Amphitheater Golden
Synaptic Mechanisms Underlying Panel • Gibbon
the Pathophysiology of Autism Inflammation as a Risk Factor for
Spectrum Disorders Psychiatric Illness
Katherine Roche (Chair), Helen Victoria Risbrough (Chair), Samantha
Bateup, Anis Contractor, Gavin Friend, Sophie Erhardt, Lilly Schwieler,
Rumbaugh Margarita Behrens
Panel • Canyon Panel • Lake
The Point of Snow Return: Long-Term Behavioral Correlates of Circuit and
Effects of Adolescent Cannabinoid Metabolic Dysfunction in Various
Exposure on Drug Addiction and Models of Traumatic Brain Injury:
Maladaptive Decision Making in Finding Common Ground
Adulthood Kaitlin Best, Amber Nolan, Akiva
Jennifer Wenzel (Chair), Jacqueline- Cohen (Chair), Edward Hall
Marie Ferland, Natalie Zlebnik Panel • Lamar
(Co-Chair), Jibran Khokhar, Christie
Navigating the Biology of
Fowler
Schizophrenia: From Genetic Risk
Panel • Cheyenne to Novel Treatment Targets
Transgenerational Inheritance of Brady Maher, Thomas Hyde (Chair),
Stress and Drug Exposure: Effects Elizabeth Tunbridge, Robert Sweet
on Brain, Behavior, and the
Panel • Talus
Epigenome
Dopamine in Reward and Learning
Lisa Goldberg (Chair), Julie Blendy,
Gregg Homanics, Chris Pierce Briac Halbout, Elizabeth Holly, David
Bortz, Kenneth Amaya
Panel • Dunraven/Obsidian
Neuroimaging Applications for Social 10:30 A.M. - 12:00 P.M.
and Affective Modulation of Pain
Smitty Stevens Ski Race • Ambush
Vitaly Napadow (Chair), Patrick
Finan, Robert Edwards 12:00 P.M. - 2:00 P.M.
Mountain Lunch • Huntley Dining
Room

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 27

WEDNESDAY, JANUARY 29, 2020, CONTINUED
3:30 P.M. - 4:30 P.M. Panel • Gibbon
Exhibits & Poster Session IV • Sex-Differences in Chronic Pain State
Jefferson/Madison From the Bench to the Bedside
Khalid Benamar, Josee Guindon
4:30 P.M. - 6:30 P.M. (Chair), Sybil Stacpoole (Co-Chair),
Panel • Amphitheater Vani Selvan
The Interaction Between Diet and Panel • Lake
Cognitive Flexibility Autism Spectrum Disorder - Bedside
Laura Corbit (Chair), Stephanie to Bench
Borgland (Co-Chair), Amy Reichelt, Angus Wilfong (Chair), Anne
Alain Dagher Anderson, Heather Born, Richard Frye
Panel • Canyon Panel • Lamar
AMPA Receptors in Synaptic There is an Aptamer for That! Nucleic
Plasticity: From Biogenesis to Acid-Based Chemosensors for
Potentiation Brain Research
Ingo Greger, Bernd Fakler, Elva Diaz, Tod Kippin (Chair), Kevin Plaxco,
Ulli Bayer (Chair) Netz Arroyo, Philip Vieira, Karen
Panel • Cheyenne Scida
Cells & Circuits Contributing to Panel • Talus
Opioid Use Disorder Adapting to Change: The Circuitry
Michael Stefanik (Co-Chair), Underlying Behavioral Flexibility
Giuseppe Giannotti, Emmanuel Darcq, Anna Radke (Co-Chair), David
Alexander Smith (Chair) Bortz (Chair), Zackary Cope, Alicia
Panel • Dunraven/Obsidian Izquierdo
Some Will Ski Down the ‘Dark Side’: 6:30 P.M. - 7:30 P.M.
Uncovering Neural Substrates of
Individual Vulnerability to Mood WCBR Business Meeting
and Anxiety Disorders (All are invited and encouraged
to attend!) • Gallatin
Marek Schwendt (Chair), Lori
Knackstedt, Jennifer Rainville, Eric
7:30 P.M. - 9:30 P.M.
Nunes
Special Poster Session & Reception •
Panel • Gallatin
Jefferson/Madison
Reward Under a Bad Sign: Neural
Mechanisms to Navigate
Motivated Action Under Risky
Conditions
Catilin Orsini, Michael McDannald,
David Jacobs, Michael Saddoris
(Chair)

28 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

THURSDAY, JANUARY 30, 2020
6:30 A.M. - 8:30 A.M. Panel • Gallatin
Board of Directors Meeting Opioid Modulation of Striatal
(Invitation Only) • Talus Circuitry Drives Diverse
Behavioral Adaptions
6:30 A.M. - 8:30 A.M. William Birdsong (Chair), Sweta
Breakfast at Leisure • Huntley Dining Adhikary, Tracy Fetterly, Aya Matsui,
Room/Peaks Restaurant Nicolas Massaly
Panel • Gibbon
7:30 A.M. - 9:30 A.M. A Role for Glia in Neuropsychiatric
Panel • Amphitheater Disorders
Spatiotemporally-Specific Patterns of Michelle Olsen (Chair), Harry
Dopamine Release Shape Action Pantazopoulos, Mikhail Pletnikov,
Selection Robert McCullumsmith
Christopher Howard, Nick Hollon, Panel • Lake
Anne Collins, Daniel Covey (Chair) Schizophrenia: Different Phenotypes
Panel • Canyon / Different Brain Systems
Advances in Cell-Type Specific Neil Cashman, George Foussias,
Detection and Manipulation of Bratislav Misic, Matthias Kirschner
Neurotransmitters (Chair)
David Root (Chair), Jason Dong, Panel • Lamar
Jonathan Marvin, Dillon McGovern, A Yardsale of Migraine and Headache
Michael Tadross Animal Models: New Models and
Panel • Cheyenne New Developments in Established
Neuronal Ensembles and Engrams in Ones
Appetitive and Aversive Behaviors Serapio Baca (Chair), Amynah
Bruce Hope (Chair), Denise Cai, Leslie Pradhan, Guido Faas, Michael
Whitaker, Melissa Malvaez, Rajtarun Morgan, Maggie Waung
Madangopal
3:30 P.M. - 4:30 P.M.
Panel • Dunraven/Obsidian
Afternoon Coffee Break • Upper
Après Concussion: Addiction-Related
Atrium
Sequelae of Traumatic Brain
Injury
Alana Conti, Christopher Olsen
(Chair), Zachary Weil, David
Pennington

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 29

THURSDAY, JANUARY 30, 2020, CONTINUED
4:30 P.M. - 6:30 P.M. Panel • Gibbon
Panel • Amphitheater Novel Models for Studying Stress
Influence on Alcohol or Substance
Big Sky High: Mechanisms of
Use Disorder
Endocannabinoid System Control
of Brain Function and Nociception Jayme McReynolds (Chair), Jessica
Loweth, Daniel Manvich, Jeffrey Tasker
Carl Lupica (Chair), Zsolt Lenkei,
Aron Lichtman, Daniel Morgan Panel • Lake
Panel • Canyon Dynamic Neural Encoding of Real-
Time Behavioral State Changes in
Kappa Opioid Receptors: The
Response to Fear- and Aversion-
Multi-Headed Gatekeepers of
Inciting Stimuli
the Nucleus Accumbens and
Motivation Jose Rodriguez-Romaguera, Lindsay
Halladay (Chair), Jonathan Fadok,
Jessica Barson (Chair), Anushree
Robert Rozeske
Karkhanis, Hugo Tejeda, Elena
Chartoff Panel • Lamar
Panel • Cheyenne Regulation of Excitability: From
Channels to Diseases
DNA Structure and Function – at the
Nexus Between Environmental Kasper Hansen (Co-Chair), John
and Genetic Risk for Gray, Tija Jacob, Terunaga Nakagawa
Neuropsychiatric Disorders (Chair)
Amelia Gallitano (Chair), Cathy
6:45 P.M. - 7:30 P.M.
Barr, Madabhushi Ram, Robert
McCullumsmith Cocktail Hour • Huntley Dining Room
Panel • Dunraven/Obsidian
7:30 P.M. - 11:00 P.M.
Sex Differences in
Neurodevelopmental Awards Banquet & Dance • Missouri
Abnormalities Arising From Early Ballroom
Life Insults
Lauren Ellman, Jared Young
(Co-Chair), Jennifer Honeycutt, Debra
Bangasser (Chair)
Panel • Gallatin
Identifying Neurobiological
Substrates of Functional
Decline to Help Develop Brain-
Interventional Approaches in
Normal and Pathological Aging
Mara Mather, Nathan Spreng, Jennifer
Bizon, Natalie Ebner (Chair)

30 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

POSTER SESSION I
SUNDAY, JANUARY 26, 2020 • Jefferson/Madison

S1. Hypothalamic POMC- S9. Synthetic Cathinone

Expressing Neurons are Mephedrone Causes Chronic
Activated by Low-Dose Ethanol Leakage of the Blood Brain
Lauren Hood Barrier by Downregulation of
S2. An Electrochemical Aptamer- Membrane-Bound Claudin-5
Based (E-AB) Biosensor Tetyana Buzhdygan
Platform for Real-Time, High S10. Pharmacotherapy Prescribing
Precision Pharmacokinetic Patterns in Alcohol Use Disorder
and Pharmacodynamic (AUD) for Patients Enrolled
Measurements Within the Brain in the Riahealth Treatment
Julian Gerson Program (RHTP)
S3. Perineuronal Net Removal Prior John Mendelson
to but Not Following Retrieval S11. Decoding Impulsive Decision-
Attenuates Cue-Induced Making: Toward Understanding
Reinstatement in Cocaine Self- No Friends on Powder Days
Administering Rats Wilder Doucette
Jereme Wingert S12. The Immediate Response to
S4. Cocaine-Induced Reinstatement Trauma in Adulthood Combined
Alters Parvalbumin Cells in With Early Life Stress Predicts
the Rat Medial Prefrontal Development of Post-Traumatic
Cortex Following Removal of Stress Disorder
Perineuronal Nets Felicia Gould
Angela Gonzalez S13. Behavioral Adaptations in a
S5. Contributions of Prelimbic- Relapsing Mouse Model of
Striatal Circuits to Sex-Based Colitis
Differences in Risk-Based Chelsea Matisz
Choice S14. Unrestricted Chemogenetic
Michael Saddoris Activation of Norepinephrine
S6. KCNQ3 Overexpression Neurons Impairs Attention
Differentially Modulates Cue- in the Mouse Continuous
Induced Reinstatement of Performance Test (rCPT)
Heroin-Seeking in High- Versus Andreas Sørensen
Low-Risk Rats S15. Examining the Mechanisms
Britahny Baskin of Spatial Working Memory
S7. Open Board Encoding and Retrieval in
S8. Gut Microbial Compositions the Prefrontal-Reuniens-
Associated With Cocaine Self- Hippocampal Network
Administration in Adult Male John Stout
Rats
Kyle Frantz

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 31

S16. Sleep Disturbances in S25. Distinct Properties of GABA-A
Mice During Chronic THC Receptors at Synaptic and
Administration and Abstinence Extraysnaptic Sites Shape
Andrew Kesner Circuit Patterns During Seizure
S17. Mesoscale Collective Action Evolution
in the Hippocampus: A David Naylor
Thermodynamic Modeling S26. Development of a Novel
Approach Locomotor Behavioral Assay
Alex Sheremet to Evaluate the Efficacy of
S18. Effects of a Natural Anti- Neurosphere-Mediated
Inflammatory Agent in a Model Regeneration Following CNS
of Alzheimer’s Disease Injury
Jason Eriksen Taylor Schanel
S19. Open Board S27. Induction of Endogenous
S20. IRF8 ASOs Modulate Microglia Reprogramming and
Responses to an Inflammatory Dedifferentiation of Adult
Insult Neurons in a Model of Spinal
Fredrik Kamme Cord Injury
S21. Fox DEN: Novel Data Sharing Jeffery Plunkett
Platform for Sharing Patient S28. Chronic Glucocorticoid
Reported Health Information Exposure Primes the
and Genetic Data From the Neuroinflammatory Response to
Largest Parkinson’s Cohort Nerve Agent Sarin
Worldwide Kimberly Kelly
Luba Smolensky S29. Damage to Thalamic Nucleus
S22. GABA and Glycine Neurons Reuniens Following Postnatal
From the REM Sleep Alcohol Exposure Suggests
Controlling Ventral Medullary Alterations to Prefrontal-
Region Inhibit Hypoglossal Thalamo-Hippocampal
Motoneurons: A Mechanism for Circuitry
Obstructive Sleep Apnea Anna Klintsova
David Mendelowitz S30. Multiple Circadian Oscillators
S23. Histological Evidence for Mediate Food Anticipation in
Diffusion Rather Than Rats
Convective (“Glymphatic”) Ralph Mistlberger
Bulk Flow of Solutes in the S31. Effects of Loss of SAP-97 and
Cerebrospinal Fluid (CSF) SAP-102 on Synaptic Plasticity
Miles Herkenham During Motor Learning
S24. Late Perampanel Treatment Yixuan Pei
Stops Midazolam-Refractory S32. AMPA Receptors Intracellular
Seizures in an Experimental Trafficking; From ER to Plasma
Model of Status Epilepticus Membrane
Claude Wasterlain Françoise Coussen-Choquet

32 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

POSTER SESSION II
MONDAY, JANUARY 27, 2020 • Jefferson/Madison

M1. Female Rats Express a More M9. Delineating the Molecular

Addictive Phenotype Than Male Architecture of the
Rats During Intermittent-Access Dopaminergic Presynapse by
Heroin Self-Administration Super-Resolution Microscopy
Timothy O’Neal Ulrik Gether
M2. Exercise Prevents Incubation of M10. Extended-Release Injectable
Cocaine and Nicotine Craving Naltrexone Before vs. After
and Multi-Triggered Relapse to Reentry for Opioid Addicted
Heroin Prisoners
Marilyn Carroll George Woody
M3. L-DOPA Decrease Oral Fentanyl M11. GluA1 Expression in Cortical-
Consumption Accumbal Circuitry of
Ryan Farero Differentially Reared Rats
M4. Proestrus-Induced Decreases in Margaret Gill
Heroin Intake in Female Rats M12. Validation of Fos-mRFP Rats
Mark Smith to Map Neuronal Ensembles
M5. Prior Cocaine Self- Underlying Reward-Related
Administration Differentially Behaviors
Alters State Encoding in Distinct Katherine Savell
Dorsomedial Striatal Neuron M13. Reward Expectation
Populations in Rats Differentially Drives
Lauren Mueller Dopaminergic Responses Across
M6. Ventral Tegmental Area Striatal Sub-Regions
Glutamate Neurons Drive Christopher Donahue
Reinforcement Absent of M14. Investigating the Role of TrkB in
Dopamine Co-Release Value-Based Decision Making
Vivien Zell Ellen Woon
M7. Perineuronal Net Degradation M15. Prefrontal Neuronal Encoding
Alters Cocaine Reinstatement of Threat-Related Stimuli Across
and Intrinsic Properties of Fast- the Estrous Cycle
Spiking Interneurons in the Rat Marieke Gilmartin
Medial Prefrontal Cortex M16. Temporal Dynamics of Spatial
Emily Jorgensen Information Encoding Within
M8. Nucleus Accumbens Cholinergic Retrosplenial Cortex
Interneurons Drive Dopamine Megha Sehgal
Release During Motivated M17. Making Sense of Computational
Approach Psychiatry
Joshua Berke Helmut Strey

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 33

M18. Neural Precursor Cell Derived M26. Characterization of a Novel
Brain-Like Tissue Induces Allelic Variant of the Human
the Formation of Long-Range Dopamine D2 Receptor
Connections in the Adult Brain Kim Neve
Gretchen Greene M27. A Semi Mechanistic
M19. Sex Differences in Body Pharmacokinetic Model to
Composition but Not Understand the Metabolic
Neuromuscular Function Conversion of Mitragynine to
Following Long-Term, 7-Hydroxymitragynine
Doxycycline-Induced Reduction Abhisheak Sharma
in Circulating Levels of M28. Can Axons Finding Their
Myostatin in Mice Way in Prefrontal Cortex in
Sonsoles de Lacalle Neurodevelopmental Disorders?
M20. The Role of Inflammation John Huguenard
Markers in Functional M29. Rare Genetic Variants in
Cortical Activation Deficits Monoamine Transports as a Risk
During Manual Tasks in Factor for Neuropsychiatric
Postmenopausal Women With Disease? Insights From a
Type II Diabetes Population Based Case-Control
Stacey Gorniak Sample
M21. Repeated Mild Traumatic Freja Herborg
Brain Injury Impairs the M30. Cocaine Actions on Cortico-
Functional Integrity of the Striatal Circuitry: A Focus on
Locus Coeruleus-Noradrenergic Cholinergic Interneurons
System Michael Authement
David Devilbiss M31. Exploration of
M22. Perampanel Treatment of Posttranscriptional and
Benzodiazepine-Refractory Translational Regulation in
Status Epilepticus Depolarized Neuroblasts
Claude Wasterlain Murray Cairns
M23. Projectile Concussive Impact M32. NRAP-1 is a Protein Ligand for
as a Preclinical Model for the NMDAR Amino-Terminal
Traumatic Brain Injury Domain
Lindsay Michalovicz Dayton Goodell
M24. CaMKII Versus DAPK1 Binding
to GluN2B in Ischemic Neuronal
Cell Death After Resuscitation
From Cardiac Arrest
Olivia Buonarati
M25. Data Archive for the BRAIN
Initiative (DABI)
Dominique Duncan

34 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

POSTER SESSION III
TUESDAY, JANUARY 28, 2020 • Jefferson/Madison

T1. Hierarchical Cue Control of T8. DG3-80: A Novel Fluorescent

Cocaine Seeking in the Face of DAT Ligand Ideal for Live
Cost Super-Resolution Microscopy
Anne Collins Amy Newman
T2. In Vivo Identification and T9. Behavioral, Autonomic,
Modulation of Appetitive and Neural Evidence of Sex
Memory-Related Circuit Differences in the Human
Elements in the Mouse Reward System
Prefrontal Cortex Katherine Warthen
Roger Grant T10. Excitatory Regulation From
T3. Investigating the Effects of the Parabrachial Nucleus to
Controllable Stress on Future the Ventral Tegmental Area
Behavioral and Neuronal Mediates Unanticipated Long-
Responses to Reward- and Drug- Term Memory of Aversion
Associated Cues Smriti Mongia
Kayla Siletti T11. Genetic Dissection Reveals
T4. Kappa-Opioid Receptor Different Roles for Intrinsic and
Antagonism Reverses Heroin Extrinsic Catecholaminergic
Withdrawal-Induced Allodynia Innervation of the Cognitive
Renata Marchette Cerebellum
T5. Intratelencephalic and Erik Carlson
Pyramidal Tract Neurons T12. VTA Glutamate Neurons
Differentially Mediate Cocaine Promote Aversion by Activation
Sensitization and Conditioned of mPFC Parvalbumin Neurons
Taste Aversion Huiling Wang
Elizabeth Crummy T13. Characterization of the Affective
T6. Neurobiological Correlates of State and Neural Correlates
Low Nicotine and Cannabis During Empathic Behavior in Rats
Exposure Stewart Cox
Hugh Garavan T14. The Dynamics of Brain
T7. Excitation of Nucleus Connectivity at Rest Underpins
Accumbens D1 Medium Spiny Performance in Task
Neurons and Facilitation of Yvonne Yau
Dopamine Release via Activation T15. The Effect of Subthalamic
of the Muscarinic M1 Receptor Nucleus Deep Brain Stimulation
Regulates Motivated Behavior on Effort Discounting
Samantha Yohn Guillaume Pagnier
T16. Mechanisms of Prefrontal
Circuit Assembly
Benita Jin

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 35

T17. Diet Modulates Brain Network T25. Expand Your Mind: Evidence
Stability, a Biomarker for Brain for Psychedelic Enhanced Brain
Aging, in Young Adults Stimulation
Lilianne Mujica-Parodi Lucas Dwiel
T18. VR Brain Exploration: Explore T26. Periaqueductal Gray and
and Manipulate a 3D Brain Nociceptive Stimulation
to Alter CNS Mechanisms of Activates Ventral Tegmental
Satiety and Hunger Area Glutamate Neurons
Bradley Tanner Leah Pappalardo
T19. Neuronal Protein Tyrosine T27. MEF2C Hypofunction in
Phosphatase 1B Drives the Neuronal and Neuroimmune
Progression of Amyloid Populations Produces MEF2C
β-Associated Alzheimer’s Haploinsufficiency Syndrome
Disease Behaviors in Mice
Alex Stewart Adam Harrington
T20. Pomalidomide Analogues to T28. Risk of Psychosis in
Mitigate Neuroinflammation in Amphetamine and
Neurodegenerative Disorders – Methylphenidate Treated Youth:
From Traumatic Brain Injury to Role of Gender
Alzheimer’s Disease Matej Markota
Nigel Greig T29. Time-Delimited Signaling of
T21. ITPKB, a Parkinson’s Disease MET Receptor Tyrosine Kinase
GWAS hit, Modulates Regulates Cortical Circuit
A-Synuclein Pathophysiology in Development and Critical
Cellular Models Period Plasticity
Warren Hirst Shenfeng Qiu
T22. Characterization of Neural T30. A Structural Basis for How
Progenitor/Stem Cell Ligand Binding Site Alterations
Monolayer and Neurosphere Can Allosterically Regulate
Cultures From Adult Brain GPCR Signaling and Engender
Tissue Functional Selectivity
Raeden Gray David Sibley
T23. Analysis of Putative Stem T31. The Effects of NMDA Receptor
and Neural Progenitor Cell Partial Agonism on rTMS Motor
Populations Following Plasticity
Traumatic Brain Injury in Adult Joshua Brown
Zebrafish T32. Overexpression of the Neural
Melanie Rojas Hammani Chaperone ProSAAS Attenuates
T24. Functional Magnetic Resonance the Transsynaptic Spread
Imaging as an Objective of Synuclein and Improves
Evaluation of Patients With Parkinson’s Symptoms in
Cerebral Palsy After Stem Cell Rodent Models of PD
Therapy Iris Lindberg
David Martinez Garza

36 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

POSTER SESSION IV
WEDNESDAY, JANUARY 29, 2020 • Jefferson/Madison

W1. Heterogeneity in Ventral Striatal W8. CRISPR/Cas9 Editing of

Subregion Encoding of Reward Neuropeptide Receptor
Taking and Seeking Signaling Reveals an Extended
Katherine Wright Amygdala Circuit Mechanism
W2. Defining How Information Modulating Alcohol Drinking,
Encoding in D1 and D2 Medium Anxiety, and Avoidance
Spiny Neurons in the Nucleus William Giardino
Accumbens Guides Motivated W9. Rat Self-Administration of
Behavior Toluene Vapor
Jennifer Zachry Kevin Braunscheidel
W3. Chronic Opiate Exposure Alters W10. Activation of the Estradiol
Mesolimbic Dopamine and Receptor, GPER1, Attenuates
Social Behavior Preference for Cocaine in Male,
Marc Pisansky but Not in Female Rats
W4. Cocaine Extinction Induces Jacqueline Quigley
Dendritic Spine Alterations W11. Sex Differences in Cholinergic
in Projection-Specific Regulation of Local Nucleus
Subpopulations in the Rat Accumbens Circuit Function
Infralimbic Cortex Controlling Motivation
Kelle Nett Lillian Brady
W5. Sex Differences in Behavioral W12. Beta-Caryophyllene: A Novel
Strategies are Accompanied Therapeutic Approach for
by Altered Neural Circuit Cocaine Use Disorder
Dynamics in Ventral Tegmental Ewa Galaj
Area to Nucleus Accumbens W13. Ethanol Induced Concentration-
Projections Dependent Effects on POMC
Amy Johnson Neuronal Excitability
W6. Effect of Lateral Hypothalamus Jonna Jackson
Excitotoxic Lesions on the W14. Modeling Motivation for
Acquisition of Sign-Tracking Alcohol in Humans Using
Behavior Traditional and Machine
Cristina Maria Rios Learning Approaches
W7. Investigating the Role of Erica Grodin
Glucocorticoid Receptor W15. Targeted Epigenetic Editing
Activation in the Propensity in the Amygdala Prevents
to Attribute Incentive Value to Adulthood Behavioral
Reward Cues Pathology Caused by Adolescent
Sofia Lopez Alcohol
John Bohnsack

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 37

W16. Cell Type Specific Role of W25. Rapid Reprogramming Method
HDAC3 Within the NAc in Differentiates CuATSM
Regulating Cocaine-Induced Responders/Nonresponders
Plasticity From ALS Patient Population
Rianne Campbell Cassandra Dennys-Rivers
W17. Epigenetic Priming Underlies W26. Pipsqueak AI: A Standardized
Transcriptional Disruption and Automated Method of
Linked to Cocaine Relapse Biomarker Quantification in
Philipp Mews Digital Histology Using Machine
W18. Endocannabinoid Signaling Learning
in a Septohabenular Circuit John Harkness
Regulates Anxiety-Like Behavior W27. A Cav2.3-Kv4.2 Complex
Casey Vickstrom Regulates A-Type Voltage Gated
W19. Psychostimulants Exert K+ Currents in Hippocampal
Dose Dependent Effects Neurons
on Frontostriatal Neuronal Jonathan Murphy
Signaling W28. Lateral Hypothalamic Fast-
Robert Spencer Spiking Parvalbumin Neurons
W20. Striatal Melanocortin-4 Modulate Nociception
Receptor Influences Action/ Through Connections in the
Habit Balance in Mice Periaqueductal Gray Area
Elizabeth Heaton Justin Siemian
W21. The Role of GIRK Signaling in W29. Gut–Brain Modulation of
Prefrontal Cortical Regulation Central Thirst Circuitry
of Affect, Cognition, and Stress Controls Satiation
Pathology: Implications for Chris Zimmerman
Therapeutic Targeting W30. The Mechanisms and
Eden Anderson Functional Consequences of
W22. Striatal Dopamine Promotes Interhemispheric Plasticity
Cognitive Effort by Amplifying Emily Petrus
the Benefits Versus the Costs of W31. LTD Requires Engagement of
Cognitive Work Two Distinct Mechanisms for
Andrew Westbrook Suppression of CaMKII Synaptic
W23. MRI-Guided Focused Targeting
Ultrasound and rAAV2-HBKO Sarah Cook
Lead to Widespread Expression W32. Biased Modulation of a Ligand-
of Transgene in the Brain Gated Ion Channel
Rikke Kofoed Riley Perszyk
W24. Angiotensin II Signaling
Potentiates GABA(A) Receptor
Activity of GABAergic Pars
Reticulata Projection Neurons
Ratan Singh

38 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Panel Session Abstracts
SUNDAY, JANUARY 26, 2020

Opening Plenary
PLENARY • SUNDAY • 8:30 A.M. - 9:30 A.M. • MISSOURI BALLROOM

How the Stroke Stopwatch was Shattered

Presenter: Gregory Albers
The last few years have seen unprecedented progress in the treatment of acute
stroke. Major advances include the 2015 endovascular trials that established
a 6-hour treatment window for endovascular therapy followed by the 2018
studies that expanded the treatment window to 24 hours using advanced
imaging. In addition, 2 studies have demonstrated that the window for
intravenous thrombolysis can be extended using advanced imaging.
The underlying theme of these advances is that every stroke evolves in a unique
manner and that imaging techniques now allow identification of patients with
salvageable tissue. Selecting patients with salvageable tissue for enrollment in
stroke studies can lead to robust treatment effects with a limited sample size.
These advances now open the door to a re-evaluation of neuroprotective
therapies as well as testing even longer time windows for reperfusion therapies.
Recent studies indicate that the assessment of collaterals using perfusion
imaging can accurately predict the speed of infarct core growth in the early
hours after symptom onset. Therefore, patients who are most likely to have
early growth can be targeted for neuroprotective therapies.
In this lecture, we will review the design and results of the most influential
recent acute stroke studies as well as the changes in stroke guidelines that
occurred as a result of these trials. We will also examine the role of advanced
imaging with automated software programs that allow rapid and accurate
determination of the volume and location of salvageable tissue.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 39

Pioneer Session # 1
PIONEER SESSION • SUNDAY • 9:45 A.M. – 11:00 A.M. • AMPHITHEATER

Understanding the Neurobiological Basis of Depression

Pioneer: Fritz Henn
Chair: Lloyd Fricker
Investigators: Bo Li, Alexander Sartorius
The presentations at WCBR began in the late 70’s with studies of GABA
and GLU uptake which suggested that asrocytes played a significant role in
controlling synaptic concentrations of GLU and GABA which was contrary
to the accepted view at the time that presynatic uptake regulated the level of
synaptic transmitter. This led to the idea of the tripartate synapse. Subsequently
we began to focus on depression and worked with an animal model developed
by Seligman, learned helplessness. Our contribution to this model was the
development of lines of animals either showing helplessness without training
or becoming resistant to the development of helplessness. Using these lines,
we mapped the circuits mediating helpless behavior and showed that inputs
from the HPA axis, hippocampus and amygdala as well as PFC converged in
the l. habenula, a small nucleus lying near the thalamus. There these signals
were integrated and processed and the output from the habenula controlled
the aminergic nuclei, regulating the release of NE, DA and 5HT. This appeared
to us to be a central pathway controlling depressive behavior and thus we
suggested that this pathway could result in relieve depression. To test this
idea, we suggested that intractable depression might be relieved by deep brain
stimulation of the l. habenula. In animal experiments we showed this to be the
case and that CAM kinase in the l. habenula appeared central to the control
of mood. This was tested in treatment resistant depression using deep brain
stimulation in the l. habenula and proved to be effective. The final work prior
to my retirement was presented at WCBR and involved showing that CAM
kinase in the l. habenula was central to maintaining a normal mood and that
when it was deleted just in that structure helpless behavior resulted, when it was
replaced normal affect resulted.

40 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Special Session
PANEL • SUNDAY • 12:30 P.M. - 2:00 P.M. • DUNRAVEN/OBSIDIAN

Conan Kornetsky’s Memorial Panel

Chair: Jacqueline McGinty
Presenters: George Koob, Linda Porrino, Chris Pierce, David Root
The scientific community lost a towering pioneer in addiction research on
December 21, 2018. Conan Kornetsky, D. Phil. was an active faculty member
and researcher in the Departments of Psychiatry and Pharmacology at Boston
University Medical School where he remained from the mid-1960s until his
retirement. Dr. Kornetsky (Conan) had a great and never diminishing love of
science. He was a great mentor to young people and he loved to ski. He received
several awards celebrating his mentorship and distinguished research record.
He was an active participant in WCBR annually for over 40 years. His research
was focused on determining the neuronal mechanisms involved in the hedonic
effects of drugs of abuse and the ways in which environmental cues influence
long-term drug effects. This panel will present fond memories of Conan’s
friendship and the famous Conan Kornetsky Ski Club at WCBR as well as
some of the pioneering research that he performed and collaborated in over
the years. Jakie McGinty will introduce the audience to Conan and his love of
WCBR. George Koob will recount his close friendship with Conan beginning
in the early 1980’s when they fast became friends at WCBR. He will recount
some of the many seminal contributions Conan made. Early on he used human
laboratory studies to identify attentional deficits in subjects with schizophrenia
laying the foundation for some of the modern attentional theories of the
disease. He then moved on to develop an animal model for measuring
thresholds for brain stimulation reward that eliminated response artefacts (rate
free brain stimulation reward threshold procedure). He followed this work by
showing that all drugs of abuse produce lower thresholds for brain stimulation
reward. Together this body of work opened the door for not only the study
of the neuropharmacology of drug reward but also the neuropharmacology
of loss of reward in addiction. Linda Porrino, a close collaborator, will discuss
Conan’s pioneering role in developing intracranial self-stimulation methods
as a means to determine pharmacological effects on brain reward and aversion
systems. She will describe recent work that continues to use these approaches to
evaluate the effects of opioids and nicotine. Chris Pierce, a former colleague at
BU, will discuss experiments examining the mechanisms of action of deep brain
stimulation in the context of its ability to attenuate the reinstatement of cocaine
seeking. This line of experimentation originated in collaboration with Conan
as we modified his self-stimulation equipment to administer the deep brain
stimulation. Conan’s contributions to WCBR were significant and those who
knew him will long remember his intellectual generosity and friendship. David

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 41

Root, the inaugural Conan Kornetsky Travel Fellow, will present phototagged
electrical recordings data and glutamate and GABA dynamics that underlie the
changes in firing during motivated behavior.

Career Development Session # 1

SPECIAL SESSION • SUNDAY • 2:00 P.M. – 3:30 P.M. • CHEYENNE

NIH Grant Application & Reviews

Chair: Brad Cooke
Participants: David Devilbiss, Lakshmi Devi, Gretchen Snyder, Paul Phillips, Dana
Plude
Attendees of this session will be provided information about the lifecycle of an
NIH grant, from brilliant idea to peer review in a study section to the release
of funding and tips on how, when, and whom to interact with at the NIH. The
session will conclude with a ‘mock’ study section that will show what happens
in a study section, and convey a few key points that can spell the difference
between a successful and unsuccessful grant application.

Sunday Afternoon Panel Sessions

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • AMPHITHEATER

Contribution of Glia to Brain Function and Disorders

Chairs: Hye Young Lee, Martin Paukert
Presenters: Yongjie Yang, Martin Paukert, Long-Jun Wu, Hye Young Lee
Glia play active and diverse roles in modulating neuronal/synaptic functions in
the CNS. This panel will discuss recent findings on novel mechanisms of glia,
particularly astrocytes and microglia, in normal and pathological brain function.
In the first part of the session, we will focus on the role of astrocytes. Yongjie
Yang will introduce a new finding on how astrocytes are regulated by neurons
through secreted neuronal exosomes. He will further discuss the neuron-
specific miR-124 in secreted exosomes in brain disease models, including
amyotrophic lateral sclerosis (ALS), and how astroglial exosomes modulate
neuronal functions. Martin Paukert will present mechanisms of behavioral
state-dependent cortical astrocyte Ca2+ dynamics. Combining timed
locomotion paradigms with pharmacological and genetic manipulations, he
revealed that α1a-noradrenergic signaling is responsible for locomotion-induced
astrocyte Ca2+ elevations, and that cholinergic signaling takes a facilitating
role. Thus, neuromodulators interact to appropriately inform astrocytes about
the behavioral state. In the second part of the panel, we will discuss about the
role of microglia. Long-Jun Wu will demonstrate that microglia in awake mice

42 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

have relatively reduced process surveillance compared with those under general
anesthesia. He will further discuss that noradrenergic tone in awake mice
normally suppresses microglial process surveillance, indicating the importance
of awake imaging for studying microglia-neuron interactions and advancing
a “set point” theory for how neuronal activity influences microglial process
dynamics. Lastly, Hye Young Lee will focus on the contribution of microglia
in the pathological condition of fragile X syndrome (FXS), the most common
monogenic cause of autism spectrum disorders. She will demonstrate an
exaggerated response of microglia to neuroinflammation in the mouse model of
FXS and how microglia contribute to the pathophysiology of FXS.

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • CANYON

Neuroendocrine and Neuroimmune Modulation in Stress

and Addiction
Chairs: Carolina Haass-Koffler, Dean Kirson
Presenters: Dean Kirson, Zoe McElligott, Kelly Cosgrove, Carolina Haass-Koffler
Increasing evidence supports the role of the neuroendocrine and neuroimmune
systems in the development of stress and addictive disorders. The stress
system has a well-established role in the addiction process by promoting
dependence-associated escalation of alcohol drinking and other addictive
substances; however, the underlying signaling mechanisms and circuitry
remain unclear, which limits therapeutic utility. This panel will provide
translational perspectives on the role of neuroendocrine and neuroimmune
modulation in the context of stress and addiction by highlighting novel
molecular mechanisms and new neural pathways connecting these systems.
Dr. Dean Kirson (Scripps Research Institute) will show how the anti-stress
neuropeptide oxytocin opposes the alcohol-induced elevation in stress-related
GABA neurotransmission in the amygdala. Dr. Zoe McElligott (University
of North Carolina) will present the role of noradrenergic signaling in stress
susceptibility and resilience. Dr. Kelly Cosgrove (Yale University) will show
the dynamic neuroimmune response to lipopolysaccharide (endotoxin) using
a novel paradigm of positron emission tomography radiotracing of the immune
sensitive protein TSPO, and how this neuroimmune response is suppressed
in individuals with addiction (tobacco smokers) and stress disorders (PTSD).
Finally, Dr. Carolina Haass-Koffler (Brown University) will present evidence
on the variation of neuropeptides including beta-endorphin, oxytocin,
substance P and orexin and the effect of appetite hormones on glucocorticoids
and mineralocorticoids in individuals with alcohol use disorder (AUD). Dr.
Haass-Koffler (Brown University) will lead discussion of the presentations,
emphasizing the translational efforts and recent advances in our understanding
of the interplay between neuroendocrine and neuroimmune modulation in
stress and addiction.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 43

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • CHEYENNE

Kratom –Potential Drug of Abuse or Useful Analgesic

Without Opioid-Like Side-Effects?
Chairs: Daniel Morgan, Jenny Wilkerson
Presenters: Christopher McCurdy, Abhisheak Sharma, Lance McMahon, Jenny
Wilkerson
Although touted as a “legal high” by some, there are innumerable anecdotal
reports of kratom use to control chronic pain, opioid addiction, and opioid
withdrawal with a limited liability profile. In February 2018, the United States
(US) Food and Drug Administration warned there was no evidence that kratom
was safe or effective for any medical use and likened its chemical compounds
to opioids. This symposium will seek to fill the knowledge gap surrounding
kratom, bringing together expert scientists to review the current knowledge
of the chemistry, pharmacology, behavioral side effects, and therapeutic
potential of kratom and at least two of its alkaloid components, mitragynine
and 7-hydroxymitragynine. Dr. Morgan will introduce the symposium. Dr.
McCurdy will review the history and chemistry of the tree that kratom is
derived from, Mitragyna speciosa. Dr. Sharma will detail what is known about
the pharmacokinetics and alkaloid composition of the natural product found in
Malaysia and currently available US commercial formulations. Dr. McMahon
will present the findings from recent rodent behavioral neuropharmacology
studies examining the reinforcing, abuse-related, and physiological effects
of kratom, mitragynine, and 7-hydroxymitragynine. Finally, Dr. Wilkerson
will present recent findings from rodent behavioral neuropharmacology
studies examining the effects of kratom and key alkaloid components for the
treatment of neuropathic pain. Upon the conclusion of these presentations, a
discussion session will evaluate both benefits and detriments attributed to this
controversial natural product, with an attempt to forge consensus on future
directions of research, emphasizing key points related to the pharmacology of
kratom. This work to better understand the complex neuropharmacology of
kratom and its alkaloids will facilitate the development of enduring chronic
pain and opioid use disorder therapeutics with a lessened abuse and untoward
physiological side-effect profile.

44 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • DUNRAVEN/OBSIDIAN

Frontal Cortical Regulation of Motivated Behaviors

Chairs: Vijay Mohan K. Namboodiri, Cody Siciliano
Presenters: Evan Hart, Cody Siciliano, Christina Gremel, Vijay Mohan K. Namboodiri
Understanding the neuronal mechanisms mediating motivated behaviors is
a major goal of neuroscience. While such behaviors are orchestrated by the
coordinated activity of multiple brain regions, the prefrontal cortex is a central
node governing such behaviors. This panel will introduce a broad audience to
recent advances in our understanding of rodent frontal cortical circuit function.
Dr. Hart will present data on the role of the rat anterior cingulate cortex (ACC)
in mediating the discrimination of options during effort-based decision-
making. Using calcium imaging and chemogenetics, these data will highlight
how activity in ACC during effort-based decision-making reflects task-specific
conditions for choice, and the effect of activation or inhibition of ACC on
choice-specific behavioral execution. Dr. Siciliano will discuss how the activity
of neurons measured using single-cell calcium imaging approaches in the mouse
medial prefrontal cortex encode stimuli with positive and negative valence.
He will then highlight how dysregulation of this process can contribute to the
development of compulsive behaviors. Dr. Gremel will present data showing
the circuit mechanisms underlying lateral orbitofrontal cortex computations
supporting goal-directed decision-making in mice. Using in vivo calcium
imaging and activity manipulations during behavior, combined with ex vivo
whole cell physiology, she will show a thalamic driven disynaptic circuit that
supports the updating of goal-directed decision-making. Dr. Namboodiri will
present two-photon calcium imaging data showing rapid timescale plasticity in
reward responses within the mouse ventromedial orbitofrontal cortex. These
data will show that select neuronal subpopulations within this region convey
reward responses as a relative comparison between a received reward and short-
term memory of previously experienced motivational stimuli. He will then
discuss how these results support our understanding of reward learning.

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • GALLATIN

Neural Systems Mediating Passive and Active Responses

During Aversive Situations
Chair: Matthew Wanat
Presenters: Lindsay Halladay, Mahsa Moaddab, Maria Diehl, Matthew Wanat
Survival in one’s environment depends upon learning and responding
appropriately during aversive situations. These behaviors can include both
defensive reactions as well as active responses to avoid the aversive outcome.
The behavioral response toward aversive stimuli is not governed by a single

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 45

brain region, but rather arises from a complex interplay between cortical,
amygdala, hippocampal, midbrain, and striatal circuits. This panel will highlight
recent research that employs electrophysiological recordings, voltammetry
recordings, chemogenetics and optogenetics to elucidate the various neural
systems that contribute to fear conditioning and active avoidance. Lindsay
Halladay (Santa Clara University) will discuss how the projections from the
infralimbic cortex to the bed nucleus of the stria terminalis enables adaptive
responding when aversive cues are ambiguous. Mahsa Moaddab (Boston
College) will present findings on the neuronal activity within the retrorubral
field during the discrimination of danger, uncertainty and safety. Maria Diehl
(Kansas State) will discuss how the projections between the prelimbic cortex,
basolateral amygdala, and ventral striatum control active avoidance. Matt Wanat
(UTSA) will discuss how distinct patterns of dopamine signaling within the
ventral medial and ventral lateral striatum are predictive of active avoidance
learning. Together, this panel will highlight the diverse neural systems that are
involved with the behavioral responding toward aversive events.

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • GIBBON

New Treatment Strategies for Mood Disorders: From IBT

to ECT
Chair: Anil Malhotra
Presenters: Anna Van Meter, Anil Malhotra, Daphne Voineskos, Miklos Argyelan
The treatment of mood disorders encompasses multiple therapeutic strategies
including psychotherapeutic, pharmacological and neuromodulatory
approaches. In this panel, we will present data across a range of treatment
modalities to provide an overview of developing work in this area. Anil
Malhotra (Hofstra/Northwell) will chair the session and provide introductory
remarks about treatment of mood disorders. Anna Van Meter (Hofstra/
Northwell) will present results from a randomized clinical trial of interpretation
bias training (IBT), a computer-based intervention designed to alter negative
emotion processing bias to improve social functioning and mood. Young adults
with bipolar disorder (N=50) randomized to IBT (versus a sham intervention)
shifted their emotion interpretation to see faces as happy, rather than sad,
and experienced reduced symptoms of depression. Anil Malhotra (Hofstra/
Northwell) will next discuss the use of novel pharmacological agents to treat
cognitive dysfunction in bipolar disorder. Data from clinical trials with the
stimulant modafinil and the dopaminergic agonist pramipexole, demonstrated
cognitive-enhancing effects. The safety profiles, which included the risk of
converting a stable patient into mania, was also favorable. Next, Daphne
Voineskos (Univ of Toronto) will discuss transcranial magnetic stimulation
(TMS), including data from a novel TMS variant, intermittent theta burst
stimulation, to treat major depression. Finally, Miklos Argyelan (Hofstra/

46 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Northwell) will conclude the session with new data on electroconvulsive
therapy (ECT). His electrical field (E-field) modeling work (n=150) revealed a
robust relationship between ECT induced E-field strength and neuroanatomical
changes that occurred during treatment. These data suggest that E-field guided
ECT may be useful to minimize cognitive side effects. Taken together, we hope
that this panel will provide a new perspective on the breadth of new treatment
approaches in mood disorders.

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • LAKE

Synaptic Transmission and Plasticity Regulated by

Neurotransmitter Receptor Auxiliary Subunits
Chair: David Bredt
Presenters: Yael Stern-Bach, Andres Maricq, David Bredt, Wei Lu
Molecular cloning initially determined that neurotransmitter-gated ion channels
comprise multimeric subunits, which contain both the ligand binding and the
ion channel functionalities. Subsequent studies identified auxiliary subunits that
regulate certain neurotransmitter receptor channels. This panel will describe
the physiological roles such auxiliary subunits play in controlling four classes of
synaptic ligand-gated ion channels.
The first presentation concerns AMPA receptors, the primary mediators of
fast excitatory synaptic transmission. Stern-Bach will discuss how members
of two auxiliary protein families, TARP and Shisa/CKAMP, independently
and combinatorially, modulate AMPA receptor function. Maricq will discuss
findings from genetic studies that provide new mechanistic insights into the
function of NMDA receptors, which control activity-dependent changes
in synaptic plasticity. Maricq’s studies identify NRAP-1, a LDLa domain
protein released by presynaptic neurons that determines synaptic strength
by modulating NMDAR gating. Nicotinic acetylcholine (nACh) receptors
mediate synaptic transmission, control neurotransmitter release and mediate
nicotine addiction. Bredt will present genome-wide expression cloning studies
that identify accessory components for several nACh receptor subtypes. He
will describe both nACh receptor chaperones and auxiliary subunits. GABAA
receptors mediate synaptic inhibition to control neural circuit information
processing and GABAA receptors are targets for numerous medicines. Whether
GABAA receptors contain auxiliary subunits that regulate trafficking, kinetics
and pharmacology has remained unknown. Lu will discuss an auxiliary subunit
of GABAA receptors that is critical for controlling these aspects of GABAA
function. Taken together this panel elaborates a general role for ion channel
accessory proteins in regulation of AMPA, NMDA, nACh and GABA receptors
and provides new insights in neurophysiology and neuropharmacology.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 47

PANEL • SUNDAY • 4:30 P.M. - 6:30 P.M. • LAMAR

New Approaches to Treating Patients in Status Epilepticus

Chair: Denson Fujikawa
Presenters: Thomas Bleck, Hilary McCarren, Claude Wasterlain, Denson Fujikawa
The approach to treating patients with status epilepticus (SE) in general, and
refractory SE (RSE) in particular, has always been to eliminate electrographic
seizure discharges (ESDs). In the case of RSE, this has been at the expense of
brain health, since the longer that SE lasts, the greater and more widespread
the neuronal necrosis, morbidity and mortality. Animal studies for the past
25 years have shown remarkable neuroprotection with NMDA-receptor
antagonists, including ketamine, in chemically or electrically induced clonic
SE in rodents, even with persistent ESDs, yet neuroprotection has never been
considered in human SE. A new antiepileptic drug (AED) to stop SE has not
been proposed in years. In addition, giving several AEDs at the onset of SE
instead of the stepwise approach of giving one at a time has not been considered
in order to prevent RCSE. Thomas Bleck will discuss the current approach
to treating SE. Hilary McCarren will discuss the use of the α2 adrenoceptor
agonist dexmedetomidine in stopping midazolam-resistant ESDs and
protecting neurons following injection of the organophosphate nerve agent
soman. Claude Wasterlain will present evidence that starting treatment with
several AEDs with complementary mechanisms of action is more effective
than a stepwise approach in stopping SE. Finally, Denson Fujikawa will present
evidence that early use of ketamine for neuroprotection in SE, shown to be
remarkably effective in the rodent, can guide a prospective clinical trial in
human SE. A biomarker for neuronal damage in the human and the rat, serum
neuron-specific enolase, could also serve as a biomarker for neuroprotection by
ketamine in human clinical trials.

Sunday Evening Panel Sessions

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • AMPHITHEATER

Pain and Itch: How are They Motivating You?

Chair: Paul Phillips
Presenters: Tamara Markovic, Amber Alhadeff, Tayler Sheahan
There is strong recognition that somatosensory processes can interact with
motivated behavior in ways that can have major impact on quality of life (e.g.,
workdays lost to chronic pain, increased risk of substance use). However,
attempts to understand the neural mechanisms linking these processes is still a
nascent field of research. The somatosensory perceptions of pain and pruritus
(itch) have often been considered to be different grades of a singular process.

48 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

However, as more is learned about the neural substrates underlying these
processes, it has become evident that they are mechanistically separable. Very
recently, evidence has emerged that circuits mediating pruritus, like those
mediating pain, interact with neural substrates of motivated behavior. This
panel will provide discussion around these points. First, Tamara Markovic
(Washington University) will describe the effects of pain on the activity of
dopamine neurons in the ventral tegmental area and how these effects drive
pain-induced anhedonia and loss of motivation for goal directed behaviors.
Next, Amber Alhadeff (University of Pennsylvania) will discuss the effects
of hunger on pain. She will describe how a subpopulation of hypothalamic
neurons expressing agouti-related protein (AgRP) selectively inhibit
inflammatory pain. Tayler Sheahan (University of Pittsburgh) will then
introduce circuitry that mediated pruritus. She will show, from studies mapping
spinal neurons that express the neurokinin-1 receptor, that a subset of these
neurons projects to brain regions where pain interacts with motivated behavior.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • CANYON

Viral Vectors for Gene Modifications to Enable Axon

Regeneration
Chair: Oswald Steward
Presenters: Kevin Park, Binhai Zheng, Oswald Steward
There is a pressing need to identify interventions that can enable regenerative
growth of CNS neurons after injury. Studies over the past decade have identified
genes that can be targeted to enhance regeneration and recent advances in viral
vector technologies are providing powerful platforms to introduce genetic
modifications in adult neurons in vivo. Challenges remain, however, because of
the molecular heterogeneity of CNS neuron types and the unique neurotrophic
properties of different viral vectors. This panel will discuss examples of the
use of AAV vector technologies to introduce genetic modifications in different
populations of CNS neurons. Kevin Park will describe approaches using viral
vectors that target different types of neurons in the visual system and how
they could be harnessed as a therapeutic intervention to regenerate a damaged
visual pathway. Binhai Zheng will discuss results from using viral vectors in
conjunction with genetically modified mice to assess the role of neuron intrinsic
and extrinsic factors in the multicellular response to spinal cord injury. Such
studies provide important in vivo evidence on molecular pathways in axon
regeneration, sprouting and astrocyte response. Oswald Steward will discuss
recent results using novel technologies involving retrogradely-transported AAVs
to deliver gene modifying cargoes to cells of origin of multiple spinal pathways
interrupted by spinal cord injury. The final part of the session will be a didactic

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 49

panel discussion on principals of AAV biology that impact on development of
effective gene modifying vectors and considerations for the potential translation
of AAV-based technologies to human therapeutics.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • CHEYENNE

It’s Not All Dopamine: The Role of Serotonin in the

Regulation of Impulsive Behavior
Chair: Katherine Nautiyal
Presenters: Catharine Winstanley, Noelle Anastasio, Katherine Nautiyal
While dopamine is generally regarded as the major modulator of impulsivity
and risky decision making, a large body of evidence now shows that serotonin
has an important role in regulating these behaviors. The multi-dimensional
aspects of these behavioral systems coupled with the complexities of
serotonin signaling make this topic timely especially as new behavioral and
neuroscience measures emerge. The goal of this symposium is to discuss
the scope and mechanisms of serotonin control over these behavioral and
cognitive systems. Dr. Winstanley will focus on the extent to which serotonin
plays a role in decision making in the cognitive effort task. Dr. Anastasio will
discuss cortiocostriatal neurocircuitry and its regulation by 5-HT2R systems
in substance use disorder behaviors, with a series of findings that collectively
indicate that the inhibition of the 5-HT2AR and/or the activation of the
5-HT2CR improve impulsivity, with collateral diminution of drug-seeking
behavior. Dr. Nautiyal will present data which help clarify the neural circuit
mechanisms of how serotonin interacts with reward systems via 5-HT1BR
signaling to influence impulsivity. Overall, the speakers will highlight advances
in our understanding of the mechanisms of serotonin control of impulsive
behavior, and the panel will discuss the implications of these findings.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • DUNRAVEN/OBSIDIAN

Long-Term Behavioral and Neurobiological Effects of

Adolescent Drug Use
Chair: Elizabeth Pitts
Presenters: Elizabeth Pitts, Anushree Karkhanis, Mary Torregrossa
Adolescence is a developmental period characterized by increased risk-
taking, impulsivity, and vulnerability to developing substance use disorders.
Additionally, emerging evidence indicates that substance use during
adolescence confers increased vulnerability across the lifespan, altering decision
making and increasing risk and severity of substance and alcohol use disorders
in adulthood. It is imperative to understand the long-term behavioral changes
following adolescent drug use, and the lasting neurobiological mechanisms

50 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

mediating these behavioral alterations, that may underlie life-long increases
in vulnerability. Our panel will present data on long-term behavioral and
neurobiological changes in rodent models observed following adolescent
exposure to 3 different drugs of abuse. We will examine commonalities and
differences in various behavioral models following exposure to a variety of
drugs of abuse during adolescence and corresponding changes in mesolimbic
circuitry. Dr. Pitts will speak about how adolescent, but not adult, self-
administration of nicotine increases anxiety-like behaviors and alcohol
consumption in adulthood and alters nAChR modulation of dopamine in the
NAc. Dr. Karkhanis will then speak about changes in adult social interaction
and dopamine release in the NAc following ethanol exposure in early and late
adolescence. Finally, Dr. Torregrossa will close the session by discussing how
Tetrahydrocannabinol (THC) self-administration in adolescence alters adult
working memory. Together, this panel will highlight the unique and lasting
impact that drug exposure during adolescence can have on behaviors and
neurobiology and explore the role these changes may play in increasing lifetime
vulnerability to substance use disorders.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • GALLATIN

Cholinergic Modulation Shapes Striatal Microcircuitry:

Roles in Reinforcement Learning and Reward-Seeking
Behavior
Chair: Samantha Yohn
Presenters: David Lovinger, Kate Wassum, Samantha Yohn, Mark Ferris
Nucleus accumbens (NAc) dopamine (DA) is an important component
of brain circuitry regulating motivated behavior and reward processing.
Cholinergic transmission and cholinergic tone is a critical regulator of midbrain
DA neuron activity, NAc DA release, and guides reward-related behavior.
Acetycholine (ACh) exerts its actions through activation of muscarinic
(mAChR) and nicotinic (nAChR) receptors. Within the NAc, cholinergic
interneurons (CINs) can initiate DA release through activation of nAChRs
on DA terminals and fine-tune output of medium spiny neurons (MSNs).
Together, these findings highlight the modulatory role of ACh on NAc
microcircuitry and behavior, and further suggest that therapeutics targeting
the cholinergic system may be beneficial in attenuating reward-related deficits
observed across several disorders. This panel aims to focus on recently
developed methods for monitoring ACh, novel therapeutics to delineate the
role of individual NAc mACh subtypes, and genetic tools to characterize
cholinergic signaling. Dr. David Lovinger will first present novel data on the
utility of the intensity-based ACh sensing fluorescent reporter (iAChSnFR)
bio-sensor to probe the function of ACh dynamics in response to drugs of
abuse, and the acquisition of a Pavlovian conditioning task. Next, Dr. Kate

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 51

Wassum will discuss how NAc ACh regulates DA release to gate the availability
of reward predictive cues. Dr. Samantha Yohn will then highlight the role of the
M1 and M4 receptors in motivated behavior through use of positive allosteric
modulators (PAMs). Finally, Dr. Mark Ferris will present data focused on
individual differences in ACh release as a predictor of motivated behavior.
Collectively, the panel provides innovative findings on the regulatory role
of ACh and its receptors on NAc DA release and DA-dependent behaviors,
which may have implications for understanding the neurocircuitry underlying
maladaptive motivation and foster the development of novel therapeutics.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • GIBBON

Investigating Brain Circuits in Neurodevelopmental

Disability, From Molecular to Electrophysiological Aspects
Chair: Francois Bolduc
Presenters: Francois Bolduc, Sarah Lippe, Jean-Francois Lepage
Neurodevelopmental disability (NDD) affects 13% of the population and
include a wide range of diagnosis from ADHD and learning disability to
intellectual disability and autism spectrum disorder. NDD is increasingly
recognized to be related to genetic etiologies. Nonetheless, the role of specific
genes in relation to specific brain regions remains unknown in most cases in
human, and often not taken into account in designing trials. We postulate that
designing interventions aiming at behaviors modification (pharmacological or
not) should include an understing of the spatio-temporal expression of the gene
(s) targeted by the intervention.
Our panel is composed of leaders in the molecular genetics and
electrophysiological investigation of Neurodevelopmental disabilities. Francois
Bolduc (University of Alberta) will present evidence for variation in molecular
expression as well as novel methods aimed at gaining a deeper understanding
of the molecular clustering in relation to brain location and temporal profile
using machine learning. He will include both human and animal model data.
Sarah Lippe (Universite de Montreal) will present findings obtained using
electroencephalography (EEG) in context of learning and memory formation
in individuals with NDD which reveal surprising characteristics of brain circuits
in NDD. Jean-Francois Lepage (Sherbrooke University) will present data from
individuals with NDD at baseline and in clinical trial obtained with EEG and
transcranial magnetic stimulation (TMS) able to correlate neuronal activity
with molecular processes including neurotransmission.
Our multidisciplinary panel will discuss how integration of molecular and
electrophysiological data with a focus on task-to-brain circuit could shed
light on cognition but also provide a better understanding of the response to
treatment in clinical trial. We will propose a new framework for the design of
trials and assessment of clinical response.

52 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • LAKE

Obesity Induced Changes to Brain Motivation Circuits

Chair: Richard O’Connor
Presenters: Richard O’Connor, Bridget Matikainen-Ankney, Morgan James
Obesity and poor dietary habits rank as a leading cause of preventable of
death in American adults second only to tobacco use. Obesity is characterized
by a dysregulation of a host of motivated behaviors, including feeding and
activity patterns that ultimately lead to caloric intake that far supersedes energy
demands. Over the past decade technological advancement in neuroscience
research tools has led to a rapid expansion of our understanding of the neuronal
motivational circuitry controlling feeding and energy expenditure. However,
how obesity reshapes communication within these neuronal networks has
not kept pace, though human and rodent behavioral data suggest obesity
imparts lasting effects on aspects of these circuits. Such persistent changes may
contribute to further weight gain, ultimately establishing obesity as a chronic
disorder. Targeting such corrupted motivational signaling may serve as a viable
therapeutic strategy for reversing the hyperphagia and motivational deficits
associated with obesity correcting caloric intake to match energy expenditure.
This panel will present unpublished emerging research characterizing obesity
induced changes to the brain’s motivational circuitry and the contribution
of such changes to the development of a range of behavioral deficits. Dr.
Richard O’Connor (Icahn School of Medicine at Mount Sinai) will present
work highlighting habenular control of obesity-related abnormalities in food
preference and motivation. Dr. Bridget Matikainen-Ankney (Washington
University School of Medicine) will discuss work outlining the effects of
weight loss after obesity on physical activity, food motivation, and underlying
accumbal circuits. Dr. Morgan James (Rutgers University) will present work
demonstrating that plasticity in the orexin-midbrain dopamine circuit underlies
enhanced motivation for palatable food in obese female rats with a history of
binge-like eating.

PANEL • SUNDAY • 7:00 P.M. - 8:30 P.M. • LAMAR

Visual Circuit Function and Plasticity

Chair: Huizhong Tao
Presenters: Jianhua Cang, Nicholas Priebe, Sandra Kuhlman, Hey-Kyoung Lee
Neural circuits in the mammalian visual system carry out complex tasks
including the reception of light and formation of monocular representations,
buildup of a binocular perception and guiding body movements in relation to
objects seen. The visual circuits can be highly sensitive to changes of sensory
experience during development as well as in adulthood. Understanding how
neurons interact within a local circuit and through long-range projections

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 53

and how they change connectivity in adaptation to dynamic environments
is essential for comprehending how the tasks are achieved. These issues are
being addressed with enriched imaging, electrophysiology, optogenetics and
behavioral approaches. In this panel, Dr. Jianhua Cang (UVA) will present
recent results regarding the visual transformations that take place in the
retinocollicular pathway, especially for the processing of motion direction. Dr.
Nicholas Priebe (UT) will discuss the computations performed by visual cortex
that integrate binocular information and generate a representation of the world
in three dimensions. Dr. Huizhong Tao (USC) will describe recent findings of
how information processing in primary visual cortex is shaped by visual input
conveyed by a higher-order thalamic nucleus pulvinar. Dr. Sandra Kuhlman
(CMU) will discuss adaptive plasticity mechanisms that improve natural
scene encoding in primary visual cortex and application of this knowledge to
rescue function in animals deprived of early visual experience. And Dr. Hey-
Kyoung Lee ( JHU) will report input-specific homeostatic synaptic adaptation
to changes in experience in visual cortex and provide evidence supporting a
metaplasticity model of synaptic homeostasis. Together, these presentations
will provide diversified views on circuit mechanisms underlying visual function
and plasticity.

MONDAY, JANUARY 27, 2020

Monday Morning Panel Sessions

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • AMPHITHEATER

Sex Differences in the Effects of Cannabis and Cannabinoid

Signaling
Chair: Ryan McLaughlin
Presenters: Aimee McRae-Clark, Elise Weerts, Ryan McLaughlin, Matthew Hill
Important sex differences exist with respect to the behavioral, biological, and
clinical effects of cannabis and cannabinoids. Despite a recent increase in
the number of studies that include sex as a biological variable, sex differences
in the effects of cannabinoids remain understudied, which has limited our
understanding of the effects of cannabinoids in females. The participants in
this panel will review data from humans and rodent models demonstrating sex
differences that render females more vulnerable to the effects of cannabinoids.
Aimee McRae-Clark will present data from clinical and human laboratory
investigations informing directions for sex-specific treatment development
for cannabis use disorder (CUD). Data suggest stress may be an important
treatment target for women with CUD. Elise Weerts will present data from
studies using positron emission tomography brain imaging to examine type-1

54 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

cannabinoid receptor (CB1R) availability in women with CUD compared
to nonusers of both sexes. In nonusers, women had higher CB1R availability
than men. Women with CUD had lower CB1R availability than women
nonusers, which correlated with the subjective effects of cannabis. Next, Ryan
McLaughlin will discuss results from preclinical studies employing a novel
model of response-contingent cannabis vapor delivery in adolescent male
and female rats. Females showed higher rates of responding and experienced
sex-specific deficits in cognitive flexibility and white matter development in
adulthood. Finally, Matthew Hill will present data on the effects of augmented
endogenous cannabinoid signaling on fear extinction in male and female rats.
Data indicate that endocannabinoid modulation has a greater impact on fear
extinction in female rats that occurs primarily via interactions with TRPV1,
as opposed to CB1R. These data reveal significant sex differences in the
cannabinoid system, effects of cannabinoids, efficacy of treatment strategies,
and their underlying mechanisms of action.

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • CANYON

Advancements in Psychedelic Neuroscience

Chair: David Martin
Presenters: David Martin, Natalie Hesselgrave, Cristopher Niell, Katrin Preller
Accumulating clinical evidence suggests that classic psychedelics may have
broad therapeutic potential in psychiatry. However, an improved understanding
of the multifaceted neural, network, and behavioral mechanisms of psychedelics
should help clarify their role in medicine, and this knowledge requires
multidisciplinary approaches. This panel’s speakers use a variety of techniques
(fMRI, calcium imaging, electrophysiology, behavioral) and species (rat,
mouse, human) to examine the consequences of psychedelic drug action at
multiple levels of inquiry. David Martin (U. Maryland) will open the panel
with data demonstrating that the 5-HT2A agonist, DOI, reverses the increased
economic demand for an opioid that stems from extended opioid experience
in a rat model. Natalie Hesselgrave (U. Maryland) will discuss her studies on
the effects of psilocybin in a mouse model of stress induced anhedonia. She
will also present data demonstrating the effects of psilocin, a pan-serotonergic
agonist, on synaptic activity in hippocampus. Cris Niell (U. Oregon) will
present results characterizing neural activity in V1 in response to visual stimuli
in awake mice under the influence of DOI. His work utilizes a combination
of calcium imaging and silicon probe electrophysiology to measure 5-HT2A
effects on cortical processing of visual information, supporting a mismatch
between bottom-up and top-down signaling. Katrin Preller (U. Zurich/Yale)
will present human behavioral and neuroimaging data acquired after the
administration of psilocybin and LSD. These data close knowledge gaps on
the neurobiology of psychedelics and their impact on cognition and emotion.

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The relevance of these results for psychedelic-assisted treatment approaches
will be discussed. In total, this panel highlights the recent developments in
5-HT2A agonist research in diverse basic and applied disciplines, with a focus
on mechanistic insight garnered from human and rodent studies.

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • CHEYENNE

Fatal Fentanyl: How One Pill Can Kill

Chairs: Phil Skolnick, Irma Cisneros
Presenters: Terrence Boos, Irma Cisneros, Kim Janda, Phil Skolnick
The title of this session paraphrases a paper (Sutter et al., Acad Emerg Med
24:106, 2017) describing the extraordinary measures required to rescue 18
patients hospitalized (one died in hospital) after ingesting tablets adulterated
with fentanyl. While the number of opioid overdose deaths appeared to
plateau in 2018, fatalities linked to fentanyl (and related synthetics) continue
to rise, now surpassing the combined total attributed to prescription opioids
and heroin. The panel will discuss both the chemical and pharmacological
properties of synthetic opioids that distinguish them from other misused
opioids and potential solutions to reduce abuse and overdose deaths. (1)
Terrence Boos (DEA) will provide an overview of the illicit manufacturing and
trafficking trends of fentanyl and its analogs and the challenges these chemicals
pose to drug regulators, including the mutability of the structure, high potency
compared to opiates like heroin, and ease of synthesis. (2) Irma Cisneros
(UTMB) has discovered the impact of chronic fentanyl self-administration on
inflammatory response and innate immunity in the neural circuitry underlying
opioid use disorder (OUD). Her data implicate immune targets in brain
that may provide novel therapeutic targets to attenuate the chronic impact
of OUD. (3) Kim Janda (Scripps) will describe the development of vaccines
and monoclonal antibodies directed at fentanyl and related synthetic opioids.
The high affinity and specificity of these biologics may be useful for relapse
prevention and overdose, while not interfering with standard medication
assisted therapies (buprenorphine, methadone). Based on a call in 2017 from
NIH leadership to develop “stronger, longer acting opioid antagonists”, (4)
Phil Skolnick (Opiant) will describe the development of intranasal nalmefene.
Structurally related to other opioid antagonists, nalmefene has pharmacological
properties that are especially well suited to counteract synthetic opioids like
fentanyl.

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PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • DUNRAVEN/OBSIDIAN

From Clusters to Stroke Busters: The Cellular, Molecular

and Translational Biology of Kv2.1/Neuregulin Complexes
Chair: Elias Aizenman
Presenters: Michael Tamkun, Andres Buonanno, Robert Fyffe, Anthony Schulien
Kv2.1 channels mediate delayed rectifier potassium currents in cortical,
hippocampal and spinal motor neurons, regulating neuronal excitability. An
additional, non-conducting function of Kv2.1 generates activity-regulated ER/
PM (endoplasmic reticulum/plasma membrane) junctions at the neuronal
surface by binding to the ER membrane protein VAP. Moreover, neuregulin
(NRG), signaling via ErbB4 receptors to modulate synaptic drive and
excitability by downregulating NMDARs and Nav channels, tightly associates
with Kv2.1 at clusters within the ER/PM junctions. Excitatory activity
and injury-mediated changes in phosphorylation status of these proteins
dramatically affect Kv2.1 channel trafficking and biophysical function, as well
as stimulate shedding of NRG from the cell surface, promoting a wide range
of effects on neurons. This panel will discuss the structural, functional and
potentially translatable features of Kv2.1/NRG-centered processes, highlighting
the diverse roles these proteins play in neuronal function and dysfunction.
Elias Aizenman (Pitt) will chair the panel and give brief introductory remarks.
Michael Tamkun (Colorado St.) will review the activity-regulated Kv2.1/
VAP interaction and then present examples of how the Kv2.1-induced ER/
PM contacts regulate calcium homeostasis, membrane protein localization,
and exocytosis. Andres Buonanno (NIH) will discuss how NMDAR and
NRG/ErbB4 bidirectional signaling can function as a homeostatic mechanism,
together with Kv2.1, to protect neurons from excitotoxicity. Robert Fyffe
(Wright St.) will discuss the roles and regulation of native Kv2.1 channels and
channel clusters at specific post synaptic sites in spinal motoneurons, across
a broad range of neuronal activity states. Finally, Anthony Schulien (Pitt) will
present the development of a Kv2.1-declustering peptide targeting the channel/
VAP association, providing long-term protection from ischemia-reperfusion
damage in a rodent model of stroke.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 57

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • GALLATIN

Molecular Adaptations Underlying Motivation and Drug-

Associated Behaviors
Chairs: Alberto Lopez, Rianne Campbell
Presenters: Alberto Lopez, Megan Fox, Rianne Campbell, Courtney Miller
Substance use disorder (SUD) is a chronic neuropsychiatric disorder
fundamentally characterized by dysregulated learning about the rewarding
properties of drugs and drug-associated cues. This maladaptive learning
manifests in cycles of persistent drug-seeking and drug-taking followed by
varying lengths of abstinence and subsequent relapse. Critically, the resilience of
drug-seeking behavior is underlined by a long-lasting interplay between altered
circuit function and maladaptive regulation of molecular and transcriptional
mechanisms. This panel proposal will present original data using multiple
novel approaches demonstrating that drugs of abuse recruit molecular and
epigenetic mechanisms to drive drug-associated behaviors. First, Dr. Alberto
López (Postdoctoral Fellow; Vanderbilt University) will outline epigenetic
and proteomic adaptations in the nucleus accumbens recruited throughout
cocaine self-administration. Dr. Megan Fox (Postdoctoral Fellow; University
of Maryland School of Medicine) will present on fentanyl-induced behavioral
and molecular adaptations linked to morphological changes in the nucleus
accumbens. Ms. Rianne Campbell (Ph.D. Candidate; University of California,
Irvine) will speak on the cell-type specific function of HDAC3, an epigenetic
modifier, in regulating cocaine-associated behaviors and cocaine-induced
plasticity in the accumbens. Finally, Dr. Courtney Miller (Associate Professor;
The Scripps Research Institute) will present new findings on a molecular motor
ATPase that remains dynamic long after formation of a methamphetamine-
associated memory, enabling selective, retrieval-independent disruption of
drug-associated memory and drug-seeking behavior. Together, this session
will highlight novel molecular and cellular techniques combined to address the
mechanisms underlying behavioral dysregulation in SUD.

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • GIBBON

Circuits and Functions of Neurons Defined by Multiple

Genetic Characteristics
Chairs: David Root, Marisela Morales
Presenters: Lief Fenno, Susana Mingote, Patricia Jensen, David Root
Advances in the detection of neuronal cell-types suggest that neurons are best
defined by multiple, rather than single genetic characteristics. This is especially
the case in the ventral tegmental area, where subsets of neurons co-transmit
dopamine and glutamate, glutamate and GABA, or singularly release dopamine,

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glutamate, or GABA. Cellular diversity has been recognized within the
locus coeruleus based on neurotransmitter content as well as developmental
progenitors. However, determining the circuits and functions of neurons
defined by multiple genetic characteristics has remained challenging. This panel
will present novel neurotechnologies and their use to label, record, and control
cell-types that are defined by multiple genetic characteristics. Dr. Lief Fenno
will describe the engineering, improvement, and characterization of next-
generation INTRSECT vectors to control neurons based on the combinatorial
presence or absence of multiple recombinases. Dr. Susana Mingote will
describe her research on mapping the anatomical and functional connections
of dopamine-glutamate neurons in the ventral midbrain and their behavioral
functions. Dr. Patricia Jensen will describe her research on a developmentally-
specific subset of noradrenergic neurons that when activated, promote a better
coping response to acute stress and decrease anxiety-like behavior. Dr. David
Root will describe his research on the circuits and behavioral functions of
ventral tegmental area neurons that co-transmit glutamate and GABA, release
glutamate without GABA, and release GABA without glutamate. Together,
this session will demonstrate how multiple recombinase driver lines together
with INTRSECT and other newly-developed genetic methods are capable
of revealing new insights into how cellular heterogeneity contributes to brain
circuitry and cell-type specific function.

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • LAKE

Rhythms on the Slope

Chairs: Kamran Diba, Andrew Maurer
Presenters: Lara Rangel, Amy Griffin, Andrew Maurer, Carmen Varela
Network oscillations are considered to reflect intrinsic circuit properties and
filtering and coordination between different brain circuits. However, as we
approach 100 years of research on these rhythms, their precise nature and
relationships to cognition remain to be determined.
During associative memory, the hippocampus must be able to integrate and
associate various streams of information. Dr. Lara Rangel performs statistical
modeling of rhythmic coordination and shows that associative learning
processes depend on coordinated oscillatory activity, and more specifically the
engagement of hippocampal cells in distinct rhythmic circuits.
Dr. Amy Griffin explores these questions in spatial working memory (SWM)
using multi-site recording from rodents. Exploring functional interactions
between the medial prefrontal cortex, the dorsal hippocampus, and the nucleus
reuniens during the encoding and retrieval phases of SWM, her study provides
insight into the physiological basis of circuit interactions and how they serve
behavior.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 59

Dr. Andrew Maurer will present data and analyses on hippocampal theta-
gamma coupling. Although the strength of coupling has been related to aspects
of memory and cognition, recent data also demonstrate a strong interaction
with velocity. His work revisits hippocampal oscillatory organization from the
perspective of the 1/f slope and challenges standard dogma regarding “slow
gamma”.
Dr. Carmen Varela examines the coupling between spindle and sharp-wave
ripple oscillations between thalamocortical and hippocampal networks during
non-REM sleep, in single units and local field potentials recorded from the
midline thalamus, medial prefrontal cortex and hippocampus CA1 of freely
behaving rats. She will discuss the functional relevance of the observed
dynamics to episodic memory.

PANEL • MONDAY • 7:30 A.M. - 9:30 A.M. • LAMAR

Neuropeptide Signaling Mechanisms: From Molecules to

Circuits to Behavior
Chairs: William Giardino, Julia Lemos
Presenters: Jenny He, Julia Lemos, Alexa Veenema, William Giardino
Neuropeptide signaling is critically important for shaping complex behaviors,
but efforts to understand neuropeptide transmission have historically been
impeded by a lack of tools. For example, neuropeptides are released from dense
core vesicles, but the nature, timing, and requirements of release remain elusive.
Further, neuropeptides signal via G-protein-coupled receptors, but the diversity
of signaling based on sex and cell type is underappreciated. Prior studies using
pharmacology and microdialysis indicated that neuropeptides are released
by salient changes in internal state or environment. Likewise, earlier evidence
suggested that neuropeptides are necessary for stress responsivity, emotional
regulation, reward learning and reproductive fitness. However, these studies
relied on methods that lacked temporal and/or spatial precision. In addition,
many studies focused on general brain areas, whereas there is now recognition
of the functional diversity of distinct neuronal populations within regions.
Our presentations highlight noteworthy technical advances that have enabled
understanding of fundamental neurobiological processes. Specifically, we will
discuss novel molecular and genetic tools used in combination with traditional
approaches to gain insight into mechanisms of neuropeptide release and
signaling across distinct circuits.
Dr. Jenny He (UCSD) will address differences in the mechanisms governing
substance P and dynorphin release from striatal direct pathway neurons. Dr.
Julia Lemos (U. Minnesota), will discuss how CRF regulates striatal cholinergic
interneurons to shape motivated behaviors in male and female mice. Dr. Alexa
Veenema (Michigan State) will present on the role of vasopressin in sex- and
age-specific regulation of social behaviors. Dr. Will Giardino (Stanford) will

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present data on circuit-level interactions between orexin/hypocretin and CRF
neuropeptide systems that modulate the stress response and facilitate addiction-
like behavior.

Monday Afternoon Panel Sessions

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • AMPHITHEATER

Genetic In Vivo Models of Neurological Disease

Chair: Stephen Traynelis
Presenters: Wayne Frankel, Stephen Traynelis, Geoffrey Swanson, Jennifer Kearney
A wide range of neurological diseases appear to involve genetic variation both
in single genes and across multiple genes and genetic control elements. In
order to understand the mechanism and treatment opportunities for such
conditions, generation of in vivo models replicating the genetic alteration
are of considerable value. This panel session will focus on in vivo models of
neurological conditions that arise from de novo variants in critical individual
genes. Dr. Wayne Frankel (Columbia University) will present functional
characteristics and interrelatedness for several mouse models of non-ion
channel childhood epileptic encephalopathy. Dr. Stephen Traynelis will discuss
an in vivo mouse model that contains a de novo GRIN2A missense variant
(S644G) identified in pediatric patients showing epileptic encephalopathy and
developmental delay. Dr. Geoffrey Swanson (Northwestern University) will
describe the behavioral, synaptic and circuit disruptions in a mouse model of a
human de novo missense variant in the GRIK2 kainate receptor subunit gene
(A657T) that is causative for intellectual disability and ataxia. Jennifer Kearney
(Northwestern University) will present in vivo data from mice harboring
a missense KCNB1 de novo variant (G379R), derived from a patient with
developmental and epileptic encephalopathy. Together these presentations
will provide broad background in terms of techniques and approaches, as well
as examples of mechanistic advances and potential treatment opportunities for
genetically defined neurological diseases.

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • CANYON

Striatal Interneurons: Orchestrating Synaptic and

Behavioral Adaptations
Chair: Brad Grueter
Presenters: Patrick Rothwell, Anne West, Brad Grueter, Brian Mathur
The striatum, a key component of the basal ganglia, is an essential hub
integrating cognitive, contextual, sensory and affective information into
behavioral outcomes. While excitatory synaptic connections drive striatal

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 61

neuron firing, inhibition and neuromodulation by interneurons are
important for coordinating and constraining neuronal excitability. Thus,
local microcircuits, particularly parvalbumin fast spiking interneurons and
cholinergic interneurons, within the striatum contribute greatly to motivated
behavior. In this panel, speakers will discuss the synaptic properties of striatal
interneurons and their contribution to behavioral outcomes. Specifically,
Patrick Rothwell (University of Minnesota) will discuss interactions between
fast-spiking interneurons and medium spiny projection neurons in the nucleus
accumbens of male and female mice, during behavioral performance of a
5-choice serial reaction time task. His results suggest fast-spiking interneurons
constrain impulsive action in this by inhibiting the output of medium spiny
projection neurons. Anne West (Duke University) will share her work
identifying the programs of gene expression and chromatin regulation induced
in parvalbumin-positive GABAergic interneurons of the nucleus accumbens
by exposure to psychostimulants, and she will discuss how this molecular
plasticity may alter the synaptic connectivity of these local circuit interneurons.
Work presented by Brad Grueter (Vanderbilt University) elucidates a novel
mechanism of GluA1 mediated synaptic plasticity at excitatory synapses onto
parvalbumin expressing fast spiking interneurons within the nucleus accumbens
and the contribution of these receptors to locomotor activation. Brian Mathur
(University of Maryland) will present emerging work on a cholinergic
interneuron microcircuit in the dorsal striatum and its role in controlling local
striatal dopamine release and behavioral reinforcement.

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • CHEYENNE

Cannabinoids, Sleep and PTSD: A Bench to Clinic Primer

Chair: Ryan Vandrey
Presenters: Andrew Kesner, Margaret Haney, Ryan Vandrey, Marcel Bonn-Miller
Research has demonstrated a clear impact of cannabis use on sleep, and this
relation appears to be particularly relevant among individuals with Cannabis
Use Disorder (CUD) and/or Posttraumatic Stress Disorder (PTSD). This
panel presentation will provide a translational evaluation of the intersection of
cannabinoids, sleep and PTSD. Dr. Kesner will discuss the role of endogenous
cannabinoid signaling on sleep stability in mice, and introduce a novel rodent
model to elucidate the neural mechanisms and behavioral consequences of
THC withdrawal-related sleep disruption. Dr. Haney will discuss the effects
of medications on a human laboratory model of cannabis withdrawal and
relapse, and will show that improving sleep during withdrawal is necessary
but not sufficient for reducing cannabis self-administration following a
period of abstinence. Dr. Vandrey will present an outpatient clinical trial in
which zolpidem improved sleep during a quit attempt and those receiving
zolpidem had clinically meaningful increases in cannabis abstinence, but sleep

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dysfunction emerged when zolpidem was stopped. Participants with past
trauma and symptoms of PTSD at intake showed improved PTSD symptom
scores if they quit cannabis use compared with those who did not quit. Dr.
Bonn-Miller will present data from two studies that used both self-report and
objective sleep assessments to demonstrate the short- (3 week) and long-term
(12 month) effects of cannabinoid use on sleep among individuals with PTSD.
Findings suggest a nuanced association between individual cannabinoids
and sleep among those with PTSD, which appears to differ from the general
population, particularly with respect to long-term outcomes. This session
addresses a timely topic, given the widespread legalization of cannabis and
hemp, and the integration of pre-clinical, human laboratory, and clinical
research on the mechanisms and complexities of how the cannabinoid system
affects sleep and health is likely to have broad appeal.

SHORT COURSE • MONDAY • 4:30 P.M. - 6:30 P.M. • DUNRAVEN/OBSIDIAN

Analysis, Visualization and Data Sharing for Human

Intracranial Recording and Stimulation
Chair: Michael Beauchamp
Presenters: Kai Miller, Dora Hermes, Dominique Duncan, John Magnotti
One of the fastest growing areas of human neuroscience is electrical recording
and stimulation of the human brain via implanted (intracranial) electrodes. This
short course will offer a tutorial introduction to these complex datasets.
Kai Miller will discuss the basic properties of the iEEG signal. Subsequently,
Dora Hermes will illustrate how these data are related to BOLD fMRI
data and will discuss what we can learn from each measurement. The Data
Archive for the BRAIN Initiative (DABI) fills the unmet need for a shared
repository for intracranial data. Dominique Duncan will discuss how DABI
offers a streamlined platform for data providers to organize, store, and
manage multimodal datasets, including clinical, demographic, imaging,
electrophysiology, and pathology data. Finally, John Magnotti will demonstrate
common iEEG analysis techniques using a purpose-built open-source tool, R
Analysis and Visualization of intracranial EEG data (RAVE).

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 63

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • GALLATIN

It’s all Downhill From Here: Dopamine Function and

Dysfunction in Movement Initiation
Chairs: Elyssa Margolis, Leslie Sombers
Presenters: Jakob Dreyer, Mark Howe, Alexandra Nelson, Leslie Sombers
Action initiation is a critical timepoint in an organism’s response to contexts
and cues. Experimentally, it is often interpreted as the time of decision. Many
neural circuits implicated in encoding decisions are also intensely studied for
their role in action initiation. This is the case in the dorsal striatum, and in
the investigation of dopamine (DA) function therein. In this panel, we will
explore new understanding of striatal function in action initiation, in both
healthy and dysfunctional states. Margolis will briefly introduce context for
the session. Dreyer will discuss new insights into basal ganglia function based
on computational modeling with a focus on the role of DA cell firing in the
generation of DA transients in the dorsal striatum. Howe will present recent,
unpublished work investigating patterns of striatal DA and acetylcholine (Ach)
signaling on multiple spatial and temporal scales in behaving mice. They find
functional heterogeneity on scales from 10s of microns to millimeters and a
dynamic coordination of DA and Ach signaling that varies with behavioral state.
Dysfunction of striatal circuits is thought to critically contribute to unwanted
spontaneous movements, for example in levodopa-induced dyskinesias in
long-term treatment of Parkinson’s disease. Nelson will describe a novel
subset of dyskinesia-related striatal neurons, identified by activity-dependent
capture of neurons in a levodopa-induced dyskinesia model. These neurons
differ in the changes in excitatory synaptic inputs and intrinsic excitability
compared to uncaptured, neighboring neurons. Finally, in the same model of
dyskinesia, Sombers will describe unpublished findings on the fluctuations in
striatal hydrogen peroxide and dopamine, and how these fluctuations relate to
abnormal movement. Together, these talks will provide updated perspectives
on the function and dysfunction of dopamine-dependent striatal signaling in
the context of movement.

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • GIBBON

Linking Endocytosis to Neuronal Survival

Chair: Elizabeth Jonas
Presenters: J. Marie Hardwick, Leonard Kaczmarek, Elizabeth Jonas, Zhenyu Yue
The process of endocytosis leads either to the recycling of membrane proteins
or to the subsequent destruction of the retrieved proteins. The latter process
is linked to the formation of late endosomes or autophagosomes. This panel
will discuss work that has revealed some molecular links that determine the

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fate of internalized membranes, including synaptic vesicles. Marie Hardwick
will discuss the role of KCTD (potassium channel tetramerization domain)
proteins, which share domains with plasma membrane potassium channels
but are not themselves ion channels. Mutations in KCTD family members
are responsible for severe neurodevelopmental disorders, and one of these,
KCTD7, has been found to regulate an autophagy-lysosome pathway in
neurons. Len Kaczmarek will describe how a presynaptic potassium channel
is required for normal endocytosis of synaptic vesicles. Human mutations in
this channel trigger abnormal endocytosis and produce neuronal death linked
to the trafficking of cell survival proteins into late endosomes and exosomes.
Elizabeth Jonas will describe how an anti-cell death protein, Bcl-xL and possibly
also the Parkinson’s protein DJ-1 enhance endocytosis to increase the size of
the neurotransmitter-containing vesicle pool and how these proteins make
trafficking decisions during presynaptic plasticity. Zhenyu Yue will speak about
how presynaptic trafficking protein Synaptojanin 1 is regulated by LRRK2
kinase, which is linked to the most common familial form of Parkinson’s
disease (PD). Phosphorylation of Synaptojanin 1 by LRRK2 disrupts
endocytosis selectively in dopaminergic neurons. He will describe how SYNJ
1 haploinsufficiency contributes to synaptic vesicle endocytosis impairment,
age dependent autophagy deficiency, alpha-synuclein accumulation, axon
degeneration and abnormal locomotor function in mice. He finds through
analysis of PD postmortem brains, that Synaptojanin 1 reduction may
contribute to the pathogenesis of PD.

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • LAKE

New Developments on Hypothalamic and Brainstem

Control of Defensive Behaviors
Chair: Avishek Adhikari
Presenters: Sung Han, Jaideep Bains, Jason Radley, Avishek Adhikari
Innate threats arise from various sources, including predators, asphyxiation and
pain. Understanding the neural circuits that coordinate reactions to these events
is vital for understanding both adaptive behaviors as well as related pathological
symptoms, such as panic attacks. We will explore how reactions to innate threats
are orchestrated by hypothalamic and brainstem circuits.
Dr. Adhikari will briefly discuss the panel’s theme, introduce the speakers and
moderate questions. First, Dr. Han will show that activity in calcitonin gene
related-peptide –expressing neurons in the parabrachial nucleus controls the
physiological and behavioral symptoms elicited by numerous panicogens in
mice. Dr. Bains will show that in mice the escape elicited by a looming disk is
preceded by an increase in the activity of hypothalamic CRH-PVN neurons
(CRH-PVN). This anticipatory increase in activity is sensitive to stressful
stimuli that have high or low levels of outcome control. These observations

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 65

indicate that CRH-PVN decode stress controllability and contribute to
shifts between active and passive innate defensive strategies. Dr. Radley will
then show that in rats the projections from the medial prefrontal cortex to
dorsal or ventral periaqueductal gray (dPAG and vPAG) respectively control
passive and active defensive behaviors elicited by a shock probe, showing
how distinct cortical-PAG projections dynamically modulate threat-elicited
defensive strategies. Lastly, Dr. Adhikari will discuss how the projection
from cholecystokinin-expressing cells in the posterior hypothalamus to the
periaqueductal gray controls escape induced by numerous innate threats.
Interestingly, this circuit can elicit organized escape through the most optimal
escape route available in geometrically complex environments.
Taken together, these data highlight the diverse and critical roles played by
evolutionarily conserved circuits in the hypothalamus and brainstem during
exposure to innate threats of multiple modalities.

PANEL • MONDAY • 4:30 P.M. - 6:30 P.M. • LAMAR

Structural, Functional and Molecular Mechanisms of

Dendritic Spine Plasticity
Chair: Yi Zuo
Presenters: Yi Zuo, Kristen Harris, Ryohei Yasuda, Jason Shepherd
Dendritic spines are the postsynaptic sites of most excitatory synapses. Their
structures and functions are regulated by experiences through a complex
network of molecular signals. The abnormal density and morphology of
spines are hallmarks of many neurological and psychiatric disorders. This
panel will focus on structural and functional plasticity of dendritic spines
under both physiological and pathological conditions. It will also discuss
molecular and local circuit changes underlying spine plasticity. Dr. Yi Zuo
(University of California Santa Cruz) will give an overview of dendritic spines
and their plasticity, and discuss in more detail the spine calcium activity during
motor skill learning and motor performance. Dr. Kristen Harris (University
of Texas at Austin) will discuss changes in resource distribution underlying
hippocampal long-term potentiation that determine where dendritic spines
cluster and protect their smaller neighbors. Dr. Ryohei Yasuda (Max Planck
Florida Institute for Neuroscience) will discuss the spatiotemporal dynamics of
postsynaptic signals underlying the growth and long-term potentiation of single
dendritic spines. Finally, Dr. Jason Shepherd (University of Utah) will present
his discovery of a novel intercellular communication mediated by Arc signaling
that describes the structure and potential function of Arc virus-like capsids. The
panel will conclude with discussion and questions.

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Special Session
SPECIAL SESSION • MONDAY • 7:00 P.M. - 8:30 P.M. • AMPHITHEATER

Improving the Climate in Scientific Disciplines

Chair: Jill Becker
Presenters: Kathryn Clancy, Paul Phillips, Jonathan Morrow, Carrie Ferrario
Overwhelming research has documented that sexual harassment happens in
the sciences; that contemptuous behaviors like gender harassment are the
most common; and that current measures intended to decrease harassment
prevalence over the last thirty years have failed. Sexual harassment has profound
consequences, personally and professionally, for individual targets as well as the
broader climate of science. A recent National Academies consensus report has
documented these findings and others, and made substantial recommendations
for change. For specific scientific disciplines to remain relevant they must
engage directly with these data and recommendations.
This session will provide an overview of the research on sexual harassment and
the main findings of the National Academies report, led by report co-author
and scientist Dr. Kathryn Clancy. Dr. Clancy will then lead a mini-workshop on
the ways in which individuals, research groups, and professional societies can
create inclusive practices that reduce tolerance for harassment. Jill Becker and
Paul Phillips (past WCBR conference chairs) will be joined by Carrie Ferrario
and Jonathon Morrow to facilitate the workshop session. This workshop is
not intended as a therapeutic space, nor will it be one where participants will
be encouraged to share personal stories. This is to keep targeted people safe
who may not otherwise be able to participate in a workshop like this. We also
recognize that discussions of this type can trigger unwanted memories or
feelings, so we counsel self-care throughout the session. Please join us to show
support for the cause of making WCBR a place where everyone can participate
in scientific discourse without restrictions.

Brain Talk Town Meeting

PLENARY • MONDAY • 7:00 P.M. - 8:30 P.M. • GALLATIN

The Transparent Time Window: A New Perspective on

Stroke Treatment
Presenter: Gregory Albers
The last 2 years have seen extraordinary advances in stroke treatment. Two large
clinical trials, that used automated software developed at Stanford University to
identify patients who have slowly evolving strokes were published in the New

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England Journal of Medicine. The goal of these trials was to expand the stroke
treatment window from a 6-hour limit up to 24 hours. This was accomplished
by determining how quickly the stroke was growing at the time the patient
arrived at the hospital and treating patients who still had salvageable tissue with
a mechanical device that removes the blood clots from the brain. Both trials
were stopped early because of overwhelming success. In DEFUSE 3 the rate of
severe disability or death was cut in half and in DAWN the rate of functional
recovery from the stroke was more than tripled.
In essence, modern imaging techniques have made the stroke treatment window
transparent for individual patients which allow therapy to be tailored based on
the specific characteristics of each stroke. These advances have led to an entirely
new approach to evaluating and treating stroke patients which has already been
adopted in over 40 countries.

TUESDAY, JANUARY 28, 2020

Tuesday Morning Panel Sessions

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • AMPHITHEATER

Broadening the Neural and Associative Mechanisms of

Fear
Chair: Melissa Sharpe
Presenters: Joshua Johansen, Melissa Sharpe, Stephen Maren, Moriel Zelikowsky
Fear research has traditionally focused on the amygdala, thought to receive
low-level information to coordinate a behavioral response to fearful stimuli.
However, as our understanding of the associative mechanisms of fear have
evolved, so too has our knowledge of the neural substrates underlying fear.
Our panel will discuss recent findings that point to unexpected players in
fear circuitry. First up, Joshua Johansen will identify a novel glutamatergic
mesencephalic reticular formation pathway involved in fear learning, which
integrates aversive sensory and defensive behavioral response information to
trigger fear learning through direct projections to lateral amygdala. This pathway
is critical to fear circuits; inactivation abolishes fear learning and reduces shock
evoked responding in amygdala. Secondly, Melissa Sharpe will demonstrate
that the lateral hypothalamus- a region thought to contribute exclusively to
feeding- becomes necessary for fear learning after a history of learning about
rewards. This is accompanied by a decrease in activity in basolateral and central
amygdala, suggesting a shift in the neural substrates encoding fear. Then,
Stephen Maren will uncover a novel prefrontal-thalamic circuit involved in
the regulation of fear after threat has passed. Specifically, Stephen will show
inactivation of the nucleus reuniens, or its afferent from prefrontal cortex,

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increases fear and prevents recruitment of hippocampal circuits necessary
for fear extinction. Finally, Moriel Zelikowsky will discuss the involvement
of Tachykinin2 (Tac2) in the persistent fear that accompanies chronic social
isolation stress. She will show that Tac2 is upregulated throughout the brain in
this model, and is necessary and sufficient for this persistent fear, with particular
relevance to PTSD. Together, this research reveals new substrates regulating fear
memories, providing an avenue for pre-clinical work aimed at treating anxiety
disorders characterized by maladaptive fear.

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • CANYON

Gene and Protein Networks in Autism and Schizophrenia

Chairs: Stephen Smith, Dan Geschwind
Presenters: James Knowles, Dan Geschwind, Stephen Smith, Lilia Iakoucheva
Neuropsychiatric disorders show enormous phenotypic and genetic
heterogeneity, but individual implicated genes are pleiotropic, affecting many
cellular functions simultaneously. Sorting pathogenic molecular pathways from
irrelevant or compensatory changes continues to be a challenge. In this panel,
we will discuss recent advances in our understanding of the gene and protein
networks implicated in neuropsychiatric disorders.
James Knowles will describe his group’s work on a collection of 255 genetically
unmodified neural progenitor cell lines derived from individuals with, and
without, schizophrenia (SCZ). The genes identified by differential expression
(DEX) analyses in these lines are significantly enriched in peaks in the PGC2
SCZ GWAS. A large number of DEX genes are involved in WNT5A signaling
and 20-40% of individuals with SCZ may have alterations in this pathway.
Dan Geschwind will speak about his group’s latest work, single nucleus
sequencing in ASD cerebral cortex using the 10x genomics platform. Their
previous work using whole tissue-based profiling showed specific patterns of
gene dysregulation in about 2/3 of cases that implicated an up-regulation of
microglia and astrocytes, and a down-regulation of specific neuronal programs.
These single nucleus data from the largest cohort to date (>30 cases and
controls), and further refine this pattern to include specific cell types and states
in ASD.
Stephen E.P. Smith will speak about his group’s work using the quantitative
multiplex co-immunoprecipitation platform to model intracellular signal
transduction pathways at the glutamate synapse. His talk will describe how
protein interaction network states are disrupted in ASD, and how these
disruptions alter the neuronal response to synaptic activity.
Lilia Iakoucheva will speak about using ASD patient-derived cerebral organoids
and CRISPR animal models to identify differentially expressed genes, proteins
and co-expression modules impacted by ASD mutations.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 69

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • CHEYENNE

Neurobiological Mechanisms Underlying the Potential

Therapeutic Effects of Psychedelics
Chair: Melissa Herman
Presenters: Mark Geyer, Samuel Slocum, William Wetsel, Harriet de Wit
Psychedelics are broadly classified as psychoactive compounds that alter
perceptions, elicit hallucinations, and/or impact affective states. Recent research
has highlighted the potential of these compounds in a number of therapeutic
applications, including treatment for depression, anxiety, and addiction.
Due to restrictive DEA scheduling, however, our understanding of the
signaling mechanisms and circuitry associated with the activity of psychedelic
compounds is incomplete. This panel will provide new perspectives on the
neurobiological actions of psychedelics by emphasizing molecular mechanisms
associated with signaling, cell type-specific actions in relevant brain regions,
and relevant behavioral paradigms. Dr. Melissa Herman (University of North
Carolina, Chapel Hill) will provide a brief introduction and lead the discussion.
Dr. Mark Geyer (University of California, San Diego) will review the recent
history and current status of the resurgence of interest and research regarding
the potential clinical applications of psychedelics such as psilocybin. Dr. Samuel
Slocum (University of North Carolina, Chapel Hill) will present his work
screening the “hallucinome”, elucidating the receptors and signaling pathways
employed by psychedelics. Dr. William Wetsel (Duke University) will present
his studies investigating the role of β-arrestins in the behavioral effects of
LSD in mice. Finally, Dr. Harriet de Wit (University of Chicago) will present
new data on the effects of LSD microdoses on EEG measures of emotional
reactivity and reward in healthy human volunteers. As the cultural significance,
clinical relevance, and therapeutic potential of psychedelic compounds are only
increasing, it is important to improve our understanding of the complexity
and diversity of their biological actions. This panel will introduce new results
highlighting recent advances in our understanding of the neurobiological
mechanisms mediating the behavioral effects of psychedelic drugs.

WORKSHOP • TUESDAY • 7:30 A.M. - 9:30 A.M. • DUNRAVEN/OBSIDIAN

Educating the Next Generation: Innovative Approaches to

Make Science Fun
Chairs: Lloyd Fricker, Sybil Stacpoole
Presenters: Ronald Harris-Warrick, Matt Carter, Karen Greif, Bradley Tanner
Today’s students have grown up using the internet, and teaching approaches
that worked for previous generations are no longer effective. Alternative
teaching approaches are also important to expand the diversity of students

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choosing careers in science and technology. This workshop will highlight
innovative techniques using active learning approaches that make science
education enjoyable and improve learning. Using the workshop format, each
speaker’s presentation will be brief in order to allow for extensive discussion.
Presentations will include metrics for assessing whether the novel active
learning approaches are effective.
The session will be moderated by Lloyd Fricker (Einstein College of Medicine),
who has developed team-based learning in a medical school curriculum, and
by Sybil Stacpoole (University of Cambridge) who brings experience with the
Oxbridge small group supervision system, an early example of active learning
adapting to modern times. Ron Harris-Warrick (Cornell U.) will describe a
variety of active learning-based approaches to enhance scientific creativity that
have been successful in undergraduate and graduate courses in a large university
setting. Matt Carter (Williams College) will describe approaches for increasing
active learning in science at a small liberal arts college environment. Karen
Greif (Bryn Mawr College) will discuss the incorporation of science ethics
and policy in courses for undergraduates as a way to make the concepts more
relevant to the students. Brad Tanner (Clinical Tools, Inc.) will describe a
virtual reality headset and computer programs for neuroscience education, from
grade schoolers to clinicians. In addition to the above presentations, ample time
will be provided for attendees to describe innovative ideas that they have used
in their teaching.

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • GALLATIN

Sex Differences in Opioid Use and Outcomes: From

Synapses to Circuits
Chairs: Matthew Hearing, Eden Anderson
Presenters: Anne Murphy, Beverly Reyes, Suman Guha, Eden Anderson
Even when taken as prescribed, opioid use carries significant risk for misuse,
dependence, and addiction. The incidence of reported heroin use and
nonmedical prescription opioid use is on the rise in recent years, however the
rate at which women are using heroin has increased to a greater extent. Until
advances are made towards filling knowledge gaps regarding neurobiological
sex differences -- both intrinsic and drug-induced -- that influence how each
sex responds to both initial and prolonged opioid exposure, progress towards
developing more targeted and impactful therapies will remain hindered.
Presenting mostly unpublished data, this diverse panel of investigators will
discuss data demonstrating sex-related overlapping and divergent effects
of opioids on drug intake and affective behavior, neuronal physiology, and
receptor signaling from the synapse to circuits and beyond. Dr. Anne Murphy
will be presenting data on the impact of biological sex and age on morphine
analgesia and the role of neuroimmune signaling. Dr. Beverly Reyes will

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 71

present data on the effect of chronic morphine on the subcellular distribution
of mu opioid receptor and corticotropin-releasing factor type 1 receptor in the
locus coeruleus of male and female rats using immunoelectron microscopy.
Dr. Suman Guha will present data showing the characterization of oxycodone
self-administration and withdrawal-associated negative affect in male and
female rats by utilizing concurrent intracranial self-stimulation, intravenous
self-administration, and data-driven behavioral analysis. Dr. Eden Anderson will
present data on sex-specific medial prefrontal cortex and nucleus accumbens
plasticity following opioid self-administration in male and female mice and the
role this plasticity has on cognitive flexibility.

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • GIBBON

Crossed Wires and Dissolving Priors: State-Dependent

Changes in Connectivity Within the Cortico-Thalamic
Network
Chair: Matthew Banks
Presenters: Matthew Banks, Katrin Preller, Anthony Hudetz, Stefanie Blain-Moraes
Current theories of brain function rely on bidirectional message passing within
the cortico-thalamic network, but the explicit roles of feedback and feedforward
pathways in perception and cognition remain unclear. Understanding how
connectivity changes with arousal state will elucidate these roles. Panelists
will present data from recent investigations focusing on sleep, disorders of
consciousness, anesthesia and psychedelic states. Matthew Banks (Univ.
Wisconsin) will present an overview of connectivity metrics, using data from
human subjects that relate structural, functional and effective connectivity
measures to explore common mechanisms of loss of consciousness under
sleep and anesthesia. Katrin Preller (Univ. Zurich/Yale Univ.) will present
data on changes in functional and effective connectivity in altered states of
consciousness induced by psychedelics such as psilocybin and LSD in human
participants, focusing on the relevance of these changes for understanding
the mechanism of action of psychedelics and their induced subjective effects.
Anthony Hudetz (Univ. Michigan) will speak about recurrent neuronal
interactions in rodent visual cortex, extending earlier findings on long-range
feedforward and feedback connectivity. He will discuss state-dependent
local communication of neuron populations as modulated by anesthetics and
analyzed by information theoretic measures. Stefanie Blain-Moraes (McGill
Univ.) will speak about patterns of feedforward and feedback connectivity
in individuals with disorders of consciousness, focusing on experiments
using anesthesia to perturb the brain networks of these patients. She will
demonstrate how patterns of spurious feedback connectivity can arise in some
patients, and emphasize the need to test the dynamic properties of functional

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connectivity patterns. The panel will foster better understanding of the role
of cortical recurrent connectivity in the healthy waking brain and in relevant
neuropsychological conditions.

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • LAKE

Stability and Plasticity in Hippocampal and Cortical

Networks
Chair: Kamran Diba
Presenters: Sebastien Royer, Gideon Rothschild, Kamran Diba, Andrew Maurer
To support adaptive behavior, the brain must balance stability and plasticity. Yet
how the functional organization and dynamics of neuronal ensembles change
with behavioral state, time and experience is poorly understood. Our panel
examines this question from a variety of angles.
First, Sebastien Royer will discuss how place cells in the dentate gyrus of the
hippocampus generate spatially selective firing fields that map the continuum
of positions in environments. He will present experimental and theoretical
evidence revealing that dentate granule cells progressively develop single evenly
dispersed place fields via competitive learning and the integration of object-
vector cell and grid cell inputs, thus encoding the specific layout of objects in a
novel context.
Next, Gideon Rothschild will present his work based on two-photon calcium
imaging of identified neuronal ensembles in the auditory cortex of behaving
mice across multiple days of exposure to stimuli. The results suggest an
unexpectedly high degree of plasticity in ensemble-level sound representations
in the cortex.
Kamran Diba will discuss the rapid spiking response of hippocampal neurons
both local and distal to focal optogenetic suppression and excitation. Findings
indicate unexpected firing increases and decreases in CA3 that are transferred
to downstream targets in region CA1. These observations are largely consistent
with inhibitory-stabilization, a frequent motif in hippocampal-cortical
networks.
Finally, Andrew Maurer will present simultaneous recordings of local field and
ripple oscillations from the CA1 and CA3 hippocampal subregions of young (4
month) and aged (24 month) rats. Preliminary data showed that the probability
of CA3-CA1 ripple co-occurrence is decreased in aged animals, suggesting that
the aged CA3 has decreased influence over CA1. ​
We conclude with an open discussion of the collective implications of these
findings for the dynamics of neuronal populations through adulthood.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 73

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • LAMAR

Glutamate Receptors: From Structure to Function

Chairs: Johannes Hell, R. Suzanne Zukin
Presenters: R. Suzanne Zukin, Sabine Spijker, August Smit, Johannes Hell
Most synapses in the brain use glutamate as neurotransmitter. Basal synaptic
transmission is mostly mediated by Na influx through AMPARs whereas
Ca influx through NMDARs leads to synaptic plasticity. Many mental and
neurological disorders are due to dysregulation of glutamate receptor function.
This panel is co-chaired by Suzanne Zukin, who will give the introduction
to glutamate receptor function, and Johannes Hell. Our panel will evaluate
different aspects of the composition and cell biology of glutamate receptors and
their regulation and function. Talks span from the role of NMDAR regulation
by PKA to mechanisms that anchor AMPARs at postsynaptic sites and their
role in synaptic plasticity. Suzanne Zukin will discuss new findings that loss of
the PKA phosphorylation site of the NMDAR GluN2B subunit impairs forms
of synaptic plasticity that require the transient insertion of Ca2+ permeable
AMPA receptors at CA1 synapses and cognition, as assessed by novel object
recognition and contextual fear conditioning. Sabine Spijker will discuss the
role of the secreted glycoprotein Noelin1 in inhibiting AMPAR lateral mobility
and how that contributes to synaptic plasticity. August (Guus) Smit will talk
about how members of the family of the Shisa (or CKAMP) auxiliary AMPAR
subunits regulate functional availability of AMPAR at postsynaptic sites.
Finally, Johannes Hell will present data on the role of alpha-actinin in anchoring
PSD-95 and with it AMPARs at the postsynaptic site.

PANEL • TUESDAY • 7:30 A.M. - 9:30 A.M. • TALUS

Heterogeneity of Midbrain VTA/SNc Cells and the

Properties Underlying Diversity of Neurotransmission
Chair: Chris Ford
Presenters: Sarah Zych, Vivien Zell, Jorge Miranda-Barrientos, Louis-Eric Trudeau
The ventral tegmental area (VTA) and substantia nigra compacta (SNc) are
comprised of a variety of neurons than can release and co-release dopamine,
glutamate and GABA. In this panel speakers will discuss recent work examining
the heterogeneity of these different neurons, the mechanisms which control
the synaptic release of their transmitters, and the differing roles these cells
play in regulating reward processing. Sarah Zych (University of Colorado) will
present data examining the properties of the synaptic co-release of dopamine
and GABA from midbrain dopamine neurons onto striatal medium spiny
neurons. By simultaneously measuring synaptic activation of D2-receptors and
GABAA receptors she will discuss how the co-release of these two transmitters

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is regulated at striatal synapses. Vivien Zell (UCSD) will discuss the relative
contribution of VGluT2-expressing (glutamate) neurons in the reinforcing
properties of the VTA. A subpopulation of VTA glutamate neurons is able to
co-release dopamine. Dr Zell has isolated glutamate transmission (absent of
dopamine release) to determine the role this population in reward processing.
Jorge Miranda Barrientos (NIDA) will talk about the diversity in the
electrophysiological properties of VTA neurons that co-express VGluT2 and
VGaT (glutamate-GABA neurons), neurons that express VGluT2 but not VGaT
(glutamate-only), and neurons that express VGaT but not VGluT2 (GABA-
only). He will discuss characterization of these cells that has allowed them
to selectively label the different phenotypes of neurons. Louis-Eric Trudeau’s
(University of Montreal) research focuses on the axonal connectivity of
dopamine neurons. In his presentation, he will present some of his recent work
on the synaptic and non-synaptic connectivity of dopamine neurons and on the
organization and regulation of glutamate synapses formed by these neurons.

Pioneer Session # 2
PIONEER SESSION • TUESDAY • 9:45 A.M. – 11:00 A.M. • AMPHITHEATER

More than 50 Years at WCBR – Brain Reward, Dopamine,

the D3 Receptor, Atypical Dopamine Transport Inhibitors,
and Cannabinoids
Pioneer: Eliot Gardner
Chair: Amy Newman
Investigators: Andrea Hohmann, Zheng-Xiong Xi
My first attendance at WCBR was in 1968 – the founding year of the
conference. My early work was on brain reward and dopamine’s involvement
in it. The next major research that occupied my time and attention was work
on the dopamine D3 receptor, and the very real possibility that highly selective
D3 receptor antagonists may have broad anti-addiction efficacy in a wide range
of preclinical animal models – work that continues to the present day. Work
on atypical dopamine transport (DAT) inhibitors as potential anti-addiction
medications followed, and continues to the present day. My attention was
then grabbed by cannabinoids and the endocannabinoid systems – with
extensive study of selective cannabinoid CB1 receptor antagonists and selective
CB2 receptor agonists as potential anti-addiction, anti-craving, anti-relapse
medications. Recently, my lab has been studying the tetrahydrocannabivarins as
potential anti-addiction, anti-craving, anti-relapse medications – with extremely
promising results. It is astounding to me to look back over the 50 years and
realize how very little we knew about the brain and behavior in 1968, how far we
have come, and how far we still need to go.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 75

Career Development Session # 2
SPECIAL SESSION • TUESDAY • 2:00 P.M. – 3:30 P.M. • CHEYENNE

Tips and Tools for Success in Academia

Chair: Lakshmi Devi
Participants: Kyle Frantz, Stephanie Borgland, Lloyd Fricker
This is a career development session focusing on “Tips and Tools for Success
in Academia”. The session is geared towards senior graduate students,
postdoctoral fellows and junior investigators, but open to scientists at all
stages of their career. Lakshmi Devi (Icahn School of Medicine at Mount
Sinai) will chair this session. The panelists include Kyle Frantz (Georgia State
University), Stephanie Borgland (University of Calgary) and Lloyd Fricker
(Albert Einstein College of Medicine). The choice of topics will be driven by
the audience, and will potentially include topics such as resolution of conflicts
(between lab personnel; data interpretation; manuscript authorship; work/life
balance), initiating and handling difficult conversations, setting up successful
collaborations, and the importance of mentoring. Audience participation will
be encouraged, both to raise topics for discussion as well as to contribute to the
discussion.

Tuesday Afternoon Panel Sessions

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • AMPHITHEATER

The Highs and Lows of GABAergic Transmission in

Anxiety: Reconciling Contradictory Findings From
Rodents and Humans Studies
Chair: Laurence Coutellier
Presenters: Elif Engin, Elizabeth Lucas, Laurence Coutellier, Georg Oeltzschner
A deep mechanistic understanding of the underlying biology of anxiety
disorders remains a “task in progress”. The majority of preclinical and clinical
studies agree on abnormal GABAergic transmission as an underlying
mechanism of fear and anxious behaviors. However, there is a lack of consensus
on the direction of these changes in inhibitory transmission, as well as their
contribution to the heterogeneous symptoms of anxiety disorders. The goal of
this panel is to provide a much needed biologically-based understanding of the
relationship between anxious behaviors and GABAergic abnormalities. We will
discuss factors that could underlie divergent findings, including brain region,
sex, and age based on state-of-the-art approaches in rodents and humans.
Dr. Engin will discuss findings in conditional knockout mice showing that

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hippocampal α2-containing GABAA receptors in CA1, CA3, and the dentate
gyrus each regulate only specific types of defensive behaviors rather than being
involved in anxiety-like behaviors unselectively. Dr. Lucas will talk about how
puberty onset and cycling gonadal hormones confer women’s susceptibility to
anxiety disorders. Her data highlight amygdala parvalbumin interneurons as a
hormone-sensitive cellular substrate driving sex differences in mice emotional
behaviors. Dr. Coutellier will summarize data obtained using DREADD and
transgenic mice showing prefrontal over-inhibition as a mechanism underlying
anxiety-like behaviors in females. Finally, Dr. Oeltzschner will present
human in vivo magnetic resonance spectroscopy (MRS) data and discuss the
interpretation of the MRS GABA signal in the context of anxiety. Altogether, we
will provide novel perspectives into GABAergic disturbances in fear and anxiety
in an effort to synergize convergent findings and to reconcile contradictory
ones. We hope to start a discussion that will provide a rationale platform for
the development of novel therapeutic strategies for those affected by an anxiety
disorder.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • CANYON

Recent Insights Into the Neurobiological Mechanisms

Underlying Opioid Self-Administration and Reinstatement
Chair: David Reiner
Presenters: Marsida Kallupi, Heath Schmidt, Jennifer Fragale, David Reiner
The current opioid crisis is fueled by use of and relapse to both prescription and
illicit opioids, particularly oxycodone and fentanyl. However, few preclinical
studies have investigated the neurobiological mechanisms underlying self-
administration and reinstatement to oxycodone or fentanyl. Based on this
gap in knowledge, we present recent findings exploring the behavioral and
neurobiological mechanisms of oxycodone and fentanyl self-administration
and reinstatement. Marsida Kallupi (UCSD) will present data on the role of
nociceptin in oxycodone self-administration and reinstatement. Marsida will
demonstrate that central amygdala injections of small molecules that target the
N/OFQ system decrease oxycodone self-administration and reinstatement
in dependent rats. Heath Schmidt (Penn) will discuss findings on the role
of glucagon-like peptide-1 (GLP-1) in oxycodone self-administration and
reinstatement. Heath will present data showing that systemic injections of
a GLP-1 receptor agonist selectively reduce oxycodone self-administration
and reinstatement without compromising antinociception, effects which are
mediated, in part, by activation of GLP-1 receptors in nucleus accumbens
shell. Jennifer Catuzzi Fragale (Rutgers) will present findings on the role of
orexin in fentanyl self-administration. Jennifer will present data showing that
intermittent-access to fentanyl induces a robust ‘addiction-like’ state that is
mediated by long term changes in the orexin system. David Reiner (NIDA)

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will describe new findings on the role of the orbitofrontal cortex in a rat model
of fentanyl relapse after contingency management. David will present data
showing that inactivation of orbitofrontal cortex decreases fentanyl seeking
after food choice-induced voluntary abstinence without affecting drug taking
during reacquisition. Collectively, this panel will highlight novel behavioral
and neurobiological mechanisms underlying opioid self-administration and
reinstatement.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • CHEYENNE

New Advances in Understanding of Orexin/Hypocretin in

Addiction: Converging Evidence From Physiological and
Behavioral Models in Multiple Species
Chairs: Morgan James, William Giardino
Presenters: Brooke Schmeichel, William Giardino, Morgan James, Sarah Leibowitz
Lateral hypothalamus neurons containing the neuropeptide hypocretin/
orexin are essential for guiding diverse forms of motivated behavior, including
drug-seeking. However, our understanding of this system in addiction has been
impeded by the immense heterogeneity of hypocretin/orexin neurons. This
panel captures recent noteworthy methodological advances enabling us to
unravel fundamental processes of the hypocretin/orexin system in motivated
behavior. We will present unpublished data from studies using novel behavioral,
physiological, and genetic approaches in combination with traditional methods
to gain insight into neural circuit mechanisms of hypocretin/orexin action in
addiction.
Dr. Schmeichel (NIDA) will address a role for hypocretin/orexin in negative
reinforcement and sleep disturbances during acute withdrawal in alcohol
dependence. Dr. Giardino (Stanford) will present data on circuit-level
interactions between the extended amygdala and the hypocretin/orexin system
that facilitate binge alcohol drinking and addiction-related behaviors. Dr. James
(Rutgers) will describe evidence that plasticity in the number of hypocretin/
orexin neurons underlies addiction to several drugs of abuse, and show
evidence supporting the repurposing of the FDA-approved dual hypocretin/
orexin receptor antagonist suvorexant for the treatment of addiction. Finally,
Dr. Leibowitz (along with her postdoc Adam Collier, Rockefeller) will present
evidence from both rodent and zebrafish models indicating that early ethanol
exposure alters the density, migration and anatomical location of hypocretin/
orexin cells, and that these changes are associated with altered addiction-like
behaviors.

78 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • DUNRAVEN/OBSIDIAN

Obesity and the Regulation of Body Weight – It’s Not All in

Your Head
Chairs: Carrie Ferrario, Lloyd Fricker
Presenters: Kevin Williams, Lloyd Fricker, Darleen Sandoval, Ian Willis
Traditionally, energy balance has been thought to be largely controlled by the
brain. Within the hypothalamus, key circuits in the regulation of body weight
are thought to include neurons expressing neuropeptide Y (NPY) which
stimulates feeding, and neurons expressing proopiomelanocortin (POMC)
which reduces feeding. However, the regulation of energy balance and body
weight are more complex. After a brief introduction by Carrie Ferrario (U
Michigan), Kevin Williams (UT Southwestern) will present recent work
examining how obesity and exercise alter POMC and NPY/AgRP neuron
function within the hypothalamus. These data support a rapid reorganization
of cellular properties in response to exercise, and hold intriguing possibilities
to facilitate adaptations to alter energy balance and glucose metabolism.
Lloyd Fricker (Einstein College of Med) will describe recent work with
mice lacking carboxypeptidase E, a major neuropeptide-producing enzyme.
Whereas mice with a global knockout of CPE are severely obese, conditional
knockout mice that lack CPE only in POMC-expressing neurons are a normal
weight, indicating that the phenotype of the global CPE knockout is not due
to alterations in POMC-derived peptides. Darleen Sandoval (U Michigan
Med Schl) will present work examining adaptations of the gut-brain axis after
bariatric surgery and the potential mechanistic role of these adaptations in the
profound weight-loss and improvements in glucose and lipid homeostasis seen
with these surgeries. In particular, she will discuss the roles of neuropeptides
secreted from the gut and hindbrain circuits that drive the metabolic success
of surgery. Finally, Ian Willis (Einstein College of Med) will describe recent
work about perturbations to RNA polymerase III transcription and the effects
on function in the brain, specifically obesity and neurodegenerative disease.
Collectively, these talks explore systems that contribute to energy balance, and
how they contribute to obesity.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 79

SHORT COURSE • TUESDAY • 4:30 P.M. - 6:30 P.M. • GALLATIN

New and Evolving Imaging Approaches for Evaluating

Neural Circuit Activity
Chair: James Otis
Presenters: Megha Sehgal, Jonathan Marvin, Vijay Mohan K. Namboodiri, James Otis
Understanding how complex brain circuits contribute to behavior in health
and disease states relies on evaluating the activity of those circuits in awake,
behaving animals. New and evolving imaging approaches now allows
simultaneous monitoring of activity in hundreds to thousands of cell-type
specific neurons in vivo, and such approaches can be combined with both
classic and newly-developed experimental techniques to identify how recorded
activity functionally relates to behavioral output. Despite the development
and improvement of these approaches over the past decade, major hurdles
limit the breadth to which we can understand neural circuit activity. Here, we
discuss advantages, limitations, and new frontiers for imaging approaches in
neuroscience, specifically related to:
(1) Microscopy, led by Dr. Megha Sehgal from University of California
Los Angeles (2) Fluorescent sensors, led by Dr. Jonathan Marvin from
Janelia Research Campus (3) Data processing and analysis, led by Dr. Vijay
Namboodiri from University of Washington (4) Behavioral models, led by Dr.
James Otis from Medical University of South Carolina.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • GIBBON

Of Shape and Function: Microtubule Remodeling in

Neurological and Psychiatric Disorders
Chairs: Candice Contet, Amynah Pradhan
Presenters: Annie Andrieux, Eleanor Coffey, Amynah Pradhan, Candice Contet
Mature neurons must maintain their highly asymmetric shape but also
remain flexible to adapt their morphology to new functional demands. This
dual capacity for stability and plasticity derives largely from the microtubule
cytoskeleton, which can be stable or dynamic. Microtubule dynamics is
modulated by post-translational modifications of tubulin and by interactions
with multiple stabilizing and destabilizing proteins. Proper orchestration of
these complex regulatory mechanisms is critical to the activity and plasticity
of neuronal circuits, and microtubule dysfunction causes pathological states.
Accordingly, microtubules have emerged as a therapeutic target for several
neurological and psychiatric disorders. In this panel, Dr. Annie Andrieux
(Grenoble Institute of Neuroscience) will discuss how the post-translational
modification of tubulin affects microtubule dynamics and control synaptic
plasticity and cognitive abilities. Dr. Eleanor Coffey (University of Turku) will

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then show how post-translational modifications to microtubule regulatory
proteins by c-Jun N-terminal kinase change in different brain regions with
behavior and circuit activity related to anxiety, depression and schizophrenia.
Dr Amynah Pradhan (University of Illinois at Chicago) will then show that
neuronal complexity in key brain regions decreases in animal models of chronic
migraine, and that histone deacetylase 6 inhibitors can restore this complexity
and inhibit migraine-associated pain and aura. Finally, Dr. Candice Contet (The
Scripps Research Institute) will talk about the effect of chronic alcohol exposure
on neuronal morphology and tubulin isotype expression in the prefrontal
cortex and show that manipulation of microtubule composition or dynamics
can alter alcohol drinking in dependent mice. Altogether, these panelists will
introduce new data highlighting recent advances in our understanding of the
regulatory mechanisms governing microtubule dynamics and their role in brain
pathologies.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • LAKE

A Better Pair of Goggles: Super-Resolution Imaging of

Synapses
Chair: Mark Dell’Acqua
Presenters: Daniel Choquet, Matthew Dalva, Katharine Smith, Mark Dell’Acqua
Synapses are the fundamental units of information processing and storage
in neuronal circuits. Despite their submicron dimensions, synapses are
structurally complex and contain thousands of different proteins that
regulate synaptic transmission, including receptors, ion channels, adhesion
molecules, scaffolds, and signaling proteins. With the advent of super-
resolution fluorescence imaging methods that break the diffraction limit of
visible light (~250 nm), such as Stimulated-Emission Depletion (STED),
Structured Illumination Microscopy (SIM), Stochastic Optical Reconstruction
Microscopy (STORM) and Photoactivation Localization Microscopy (PALM),
neuroscientists gained unprecedented abilities to interrogate sub-synaptic
structure, organization, dynamics, and function on the nanometer scale,
including how postsynaptic receptors are aligned across the synaptic cleft with
sites of presynaptic neurotransmitter release. In particular, it is thought that this
nanoscale organization of receptors is crucial for tuning synaptic transmission.
Daniel Choquet (CNRS U. Bordeaux) will present new results combining
super-resolution imaging and electrophysiology to further define the links
between the regulation of AMPA receptor nanoscale dynamic organization and
excitatory synaptic plasticity. Next, Matthew Dalva (Thomas Jefferson Univ.)
will present new results that begin to resolve how the nanoscale organization
of excitatory synapses in dendritic spines changes following spine structural
plasticity. Katharine Smith (Univ. Colorado) will then present new work
characterizing how GABAA receptors and pre- and postsynaptic scaffolds are

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 81

organized into sub-synaptic nanodomains at inhibitory synapses and how
this changes during plasticity. Finally, Mark Dell’Acqua (Univ. Colorado) will
present new findings showing how palmitoylation of the postsynaptic kinase-
phosphatase scaffold protein AKAP79/150 regulates its nanodomain targeting
and mobility dynamics at excitatory synapses.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • LAMAR

Why Can’t You Hear Me? “Auditory” Circuits in Health and

Disease
Chairs: Patrick Kanold, Li Zhang
Presenters: Merri Rosen, Jan Schnupp, Shaowen Bao, Gregg Recanzone
The central auditory system is fundamental for human communication and
malfunction of auditory circuits is associated with many diseases. However,
malfunction of auditory perception involves many areas outside the canonical
auditory system. In this panel, we will discuss the circuits and function of
cortical and subcortical auditory processing centers and how their function is
impacted or improved by experience, stress, hearing loss, etc. Dr. Patrick Kanold
(Univ. Maryland) will discuss how developmental exposure to sound stimuli
shapes the circuits of the auditory cortex. Dr. Merri Rosen (NEO MED) will
discuss the detrimental effects of early life stress on the auditory system and
its interactions with early hearing loss. Dr. Jan Schnupp (City U., Hong Kong)
will discuss how the auditory system can adjust to artificial stimulation with
cochlear implants (CIs) and how the mature, deaf auditory system can rapidly
develop essentially normal binaural sensitivity with CIs despite a lack of hearing
experience in early life. Dr. Li Zhang (USC) will discuss a noncanonical central
auditory pathway and its function. Dr. Shaowen Bao (U. of Arizona) will discuss
how noise-induced hearing loss alters auditory cortical circuits and function.
Dr. Gregg Recanzone (UC Davis) will discuss changes in central auditory
pathways as a function of aging in primates.

PANEL • TUESDAY • 4:30 P.M. - 6:30 P.M. • TALUS

Dopaminergic Modulation of Learning and Cognition

Chairs: Munir Kutlu, Amy Johnson
Presenters: Munir Kutlu, Daniel Covey, Stephanie Borgland, Joshua Berke
The involvement of dopamine in reward processing and addiction has been
well established by a large literature suggesting that dopamine neurons encode
reward prediction error. However, recent evidence suggests that dopamine plays
a broader role encompassing multiple facets of learning and cognition. Here,
our panel will highlight new and exciting research underlying how dopamine
encodes information during learning of bimodal reward as well as bimodal

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outcomes. First, Dr. Munir Gunes Kutlu will showcase novel research on how
nucleus accumbens (NAc) dopamine shapes attentional components of reward
and aversive learning. Next, Dr. Daniel Covey will show that mesolimbic
dopamine transmission not only drives goal-directed behavior but also encodes
the information related to this type of learning. In addition, we will present
data showing the effects of upstream and downstream modulators of dopamine
on decision making and reinforcement learning. Specifically, Dr. Stephanie
Borgland will present data suggesting that lateral hypothalamic orexin and
dynoprhin projections onto ventral tegmental area (VTA) dopamine neurons
controls reward-seeking behavior and determines reinforcer- and cue-driven
behaviors. Finally, Dr. Joshua Berke will present new data from his laboratory
investigating how NAc cholinergic interneurons mediate dopamine release
during adaptive decision making under distinct cognitive demands of spatial
foraging. Overall, our panel will offer a new framework of the multifaceted
action of pre- and postsynaptic dopamine in learning and cognition that
supersedes dopamine signal as solely encoding the error of predicted outcomes.

Tuesday Evening Panel Sessions

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • AMPHITHEATER

Reacting to the Bumps: Diverse Mechanisms Through

Which Different Systems Maintain Homeostasis
Chair: Shane Hentges
Presenters: Zachary Knight, Matt Carter, Stephanie Padilla, Andrew Rau
The body’s ability to maintain a relatively stable internal environment is
remarkable. From nutrient and fluid sensing to temperature regulation
and cyclic regulation of sleep and hormones. The breadth of mechanisms
used to achieve homeostasis is notable and the panelists will highlight their
latest findings regarding adaptive responses in various homeostatic systems.
Zachary Knight (UCSF/HHMI) will share results from his research on
neural mechanisms that govern hunger and thirst. He will discuss results from
calcium imaging studies demonstrating that key homeostatic neurons receive
sensory information from the outside world, which they use predict impending
physiologic changes and adjust behavior preemptively. He will discuss how
these homeostatic circuits integrate external sensory cues with internal signals
arising from the body in order to generate and shape goal-directed behaviors.
Matt Carter (Williams College) will discuss his work aimed at understanding
the interaction between feeding and sleep circuits. He will share recent work
showcasing how feeding-related neurons in the arcuate nucleus affect sleep/
wake behavior, as well as new work about how different states of sleep and
arousal affect these neurons in freely moving animals. Stephanie Padilla
(University of Massachusetts) will discuss her work on the influence of steroid

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 83

hormones on thermal regulation. She will present data using functional circuit
mapping techniques to define the neurons, circuits and signaling molecules that
lead to vasomotor responses in awake behaving mice. Andrew Rau (Colorado
State University) will present work highlighting the role of the fast-acting
transmitters GABA and glutamate in the regulation of hypothalamic POMC
neurons. He will show that POMC neurons receive a significant GABAergic
input from the dorsomedial hypothalamus, while glutamatergic inputs largely
originate from the VMH. He will then discuss how these inputs affect, and are
affected by, food intake.

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • CANYON

Computational Models of Inhibitory Control

Chair: Alain Dagher
Presenters: Michael Frank, Valerie Voon, Frederike Petzschner
Inhibitory control is thought to be an important process in a number of
psychiatric and medical conditions, including addiction, obesity, Parkinson’s
Disease and Pathological Gambling. Recent computational approaches have
allowed researchers to model inhibition in a variety of ecologically relevant
tasks. Speakers will present new data from healthy participants and individuals
with obesity, problem gambling, obsessive-compulsive disorder, and Parkinson’s
Disease.
Chair, Alain Dagher will briefly introduce the evidence that impaired inhibitory
control is a common trait across a variety of neuropsychiatric disorders.
Michael Frank will present computational models on frontal - basal ganglia
interactions to support cognitive control over action selection. He will use
multiple levels of description, linking neurophysiological signatures of spiking
and oscillations to inhibitory control and modulation of decision thresholds.
Valerie Voon will show that intentional inhibition, although poorly understood,
represents a highly ecologically valid process underlying daily actions and
pathological processes. She will present intracerebral recordings from
Parkinson’s disease during deep brain stimulation surgery of the subthalamic
nucleus. Recordings during voluntary inhibitory control reveal new insights
about the role of the subthalamic nucleus in cortico-striatal motor control.
Frederike Petzschner will provide evidence that disorders such as pathological
gambling and obsessive-compulsive disorder are centered around a failure of
inhibitory control. She will show that impulsive and compulsive tendencies
may be dissociated using a novel experimental design in combination
with computational models of structure learning in pathological gamblers,
recreational gamblers and participants with obsessive-compulsive traits.

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PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • CHEYENNE

Candidate Neuroimaging Biomarkers for

Synucleinopathies
Chairs: Daniel Huddleston, Xiaoping P. Hu
Presenters: Xiaoping P. Hu, Daniel Huddleston, Kejal Kantarci
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are
progressive neurodegenerative diseases characterized pathologically by the
accumulation of alpha-synuclein aggregates in the brain. They are therefore
referred to as synucleinopathies. Emerging MRI and radionuclide imaging
markers of symptomatic and prodromal synucleinopathy show promise for
clinical and translational applications.
Presenter #1: Xiaoping Hu, PhD, Quantitative Neuromelanin-sensitive MRI
Neuromelanin-sensitive MRI is a technique that has been used to assess
neurodegeneration in substantia nigra (SN) and locus coeruleus (LC). This talk
will discuss the technique, followed by a review of its applications in the study
of SN and LC in synucleinopathy research. Its reproducibility and application in
region of interest selection will also be discussed.
Presenter #2: Dan Huddleston, MD, Brainstem MRI Markers of Prodromal and
Manifest Synucleinopathy
Neuroimaging markers of brainstem pathology have potential applications for
subject selection and as surrogate outcome measures to enhance the success
of neuroprotective therapeutics trials for synucleinopathies. Neuroimaging
measures sensitive to prodromal neurodegeneration may enable clinical
trial designs for therapeutics designed to prevent PD, DLB and multiple
system atrophy. This talk will review candidate brainstem MRI markers of
neuromelanin, iron and microstructural disease pathology with potential
applications in these areas.
Presenter #3: Kejal Kantarci, MD, Radionuclide and MR Imaging Markers of
Cortical and Subcortical Pathology in Synucleinopathy
Radionuclide imaging allows in vivo assessment of metabolism and other
molecular aspects of neurodegeneration. FDG-PET and arterial spin labeling
MRI detect signatures of regional cortical hypoperfusion, and may assist
both clinical diagnosis and therapeutic trial design. Dopamine transporter
imaging also shows promise for prodromal detection and monitoring of
synucleinopathies.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 85

WORKSHOP • TUESDAY • 7:00 P.M. - 8:30 P.M. • DUNRAVEN/OBSIDIAN

Life Science Entrepreneurship: Should You Take the Slope

That Leads to Commercialization?
Chair: Bradley Tanner
Presenters: Bradley Tanner, Jason Eriksen, Susan Tappan
Concept: A Career Development Workshop for neuroscientists who are
considering pursuing entrepreneurship and commercialization.
Goal and Experience: The goal is to help life scientists at different points in their
career become aware of and able to investigate entrepreneurial career options
that utilize their unique talents. This is a planning and discussion workshop
requiring active thought, participation, and contribution; this a not a lecture
or a set of personal stories. Every entrepreneur carves their own path down the
entrepreneurial slope.
Participants can: 1) assess the steepness and challenge of an entrepreneurship
slope, 2) determine if going down that slope is something they might want to
attempt. Entrepreneurship is NOT the “best” slope for everyone; only the life
scientist can make that decision, 3) [if entrepreneurial intent exists], identify
the equipment they lack and specific challenges that they will encounter, build
their confidence in taking on the challenges, and layout a plan including the
potential of grabbing the NIH SBIR flag at the bottom!
We highlight NIH SBIR funding because the bar to obtaining a Phase I SBIR
is low compared to angel, VC or Private Equity funding. Scientists are already
excellent grant writers and universities and the government have tremendous
resources to support an SBIR application.
Presenters: Bradley Tanner, MD, ME is a psychiatrist with a wealth of 25
years of SBIR experience including on SBIR review panels. His company has
received multiple SBIR Phase I and Phase II awards stretching back to 1995
and totaling over $20 million. Jason Erikson, Ph.D. is a regular WCBR attendee
and Ph.D. neuroscientist who has founded 2 companies [both still active] and
is working on a third company seeking SBIR funding. Susan Tappan, Ph.D. is
Scientific Director at MBF Bioscience and has a broad interest in developmental
neuroscience with a focus in neuroanatomy.

86 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • GALLATIN

Ventral Striatum Dopamine Encoding of Learning and

Motivated Behaviors
Chair: Ryan Farero
Presenters: Matthew Wanat, Ryan Farero, Erin Calipari
Ventral striatum dopamine release is a fundamental neural signal mediating
the acquisition and maintenance of reinforced behaviors. Aberrant signaling of
dopamine within the ventral striatum is hypothesized to contribute to an array
of mental illnesses. As such investigations on the role of dopamine transmission
in normal and pathological mental function is important to elucidate potential
targets for the development of therapeutic strategies for mental illness. This
panel will present studies that examine dopamine transmission within the
nucleus accumbens during reinforced behaviors, and how these signals
contribute to learning and motivation during rodent behavioral assays. First,
Matt Wanat (UTSA) will present data investigating the role of ventral striatal
dopamine signaling in changing subjective preference. Next, Ryan Farero
(UW) will describe data examining the role nucleus accumbens core dopamine
transmission has on addiction-related behaviors during the presentation of drug
associated stimuli. Lastly, Erin Calipari (Vanderbilt University) will discuss
data using in vivo optical tools to demonstrate the integration of signals within
the ventral striatum that encode salience and novelty, during reinforcement
controlled by positive and negative stimuli. Together this panel will discuss a
range of behavioral assays that examine ventral striatum dopamine encoding of
reinforced behaviors in normal and pathological animal models.

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • GIBBON

Regulation of Motivation for Food, Sex and Drugs by

Ovarian Hormones
Chairs: Yanaira Alonso-Caraballo, Tracy Fetterly
Presenters: Jill Becker, Annabell Segarra, Yanaira Alonso-Caraballo
Female neurobiology is understudied in biomedical research. Consequently,
critical gaps remain in our understanding of the mechanism of how ovarian
hormones and the reproductive cycle regulate motivated behaviors, reward
learning, and corresponding plasticity. Cyclic changes in ovarian hormones
potently regulate brain circuits for motivation to pursue sex, and they are
key regulators of motivation for food cues and drugs of abuse. This panel will
discuss our latest understanding of the mechanistic underpinning of how
the estrous cycle and ovarian hormones modulate reward and motivation in
mesocorticolimbic brain circuits. First, Dr. Jill Becker (University of Michigan),
will present new data on the interaction between estradiol, estradiol receptors

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 87

and dopamine transmission that regulate motivational competition for sex
or food. Next, Dr. Annabell Segarra (University of Puerto Rico) will describe
studies on how age and sex shape estradiol-induced neuroplasticity. Finally,
Yanaira Alonso-Caraballo (University of Michigan) will describe changes in the
excitability of medium spiny neurons in the nucleus accumbens during different
phases of the estrous cycle and how they relate to changes in processing of
food-cues in rat models of obesity. Tracy Fetterly will provide introductory
comments and lead discussion of the presentations. Together this panel will
summarize our latest understanding of brain mechanisms for how the estrous
cycle and ovarian hormones shape motivational arousal, and flexible decision
making.

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • LAKE

Epileptology: From Basic Science to Applied

Bioengineering
Chair: Olaf Paulson
Presenters: Claude Wasterlain, Lars H. Pinborg, Sándor Beniczky
Olaf Paulson will provide introductory comments and lead the discussion of the
presentations.
This session will highlight exciting recent advances in epileptology, from basic
science and understanding of epileptogenesis, to automated seizure detection
and characterization using wearable devices.
Claude Wasterlain: Epileptogenesis: In Search of the Holy Grail
Finding an antiepileptogenic treatment remains the Holy Grail of epilepsy. We
will review current evidence about the basic mechanisms of epileptogenesis, the
nature of the latent period and the hippocampal networks involved in animal
models of acquired focal epilepsy. We will review the filter hypothesis, which
postulate that hippocampal lesions compromise neural networks which prevent
excessive build-up of excitation and seizures.
Lars H. Pinborg: The Cognitive, Behavioral and Psychiatric Comorbidities of
Epilepsy: How Can We Improve?
It is increasingly recognized that the burden of epilepsy is more than just
seizures. In particular, depression has been demonstrated to be more predictive
for patient’s quality of life than seizures. Cognitive and behavioral problems
are related to poor psychosocial outcome and stigmatization. Is it possible
to identify patients at special risk of developing comorbidities and initiate
preventive strategies so early in the disease process that the outcome of epilepsy
improves significantly? Review of the literature and possible future directions
are discussed.
Sándor Beniczky: Automated Seizure Detection and Characterization Using
Wearable Devices

88 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

This presentation will review the published evidence for the accuracy of
automated seizure detection and risk assessment of epileptic seizures, and it will
highlight future developments in this field.

PANEL • TUESDAY • 7:00 P.M. - 8:30 P.M. • LAMAR

Autism Spectrum Disorder: Mechanisms and Potential

Treatments
Chairs: Hsiao-Huei Chen, Brigitta Gundersen
Presenters: Brigitta Gundersen, Hui-Chen Lu, Hsiao-Huei Chen, Evdokia Anagnostou
Autism Spectrum Disorders (ASD) are incredibly heterogenous, differing in
symptoms, trajectories, and underlying etiologies. Brigitta Gundersen (Simons
Foundation) will introduce the panel and summarize the current status of
research from the SPARK Consortium and other cohorts that highlight ASD
risk genes, raising key questions and challenges for ASD treatment. The next 3
presentations discuss novel targets for therapeutic intervention in ASD, from
growth factors to a phosphatase affecting synaptic function, E:I balance and
neural circuits and new clinical trials targeting these mechanisms.
Hui-Chen Lu (University of Indiana) will share her findings that focus on
how glutamate transmission affects dendritic patterning through the activity
of fibroblast growth factors (FGFs)/FGF receptors (FGFRs) as a possible
treatment approach for autism and stress-related psychiatric disorders.
Hsiao-Huei Chen (Ottawa Hospital Research Institute) will present new
evidence that protein tyrosine phosphatase PTP1B activity in parvalbumin
interneurons affects E:I balances and causes homeostatic maladaptation of
inhibitory circuits to impede information processing at the anterior cingulate
cortex associated with autism-like behaviors in mice. PTP1B is a phosphatase
that disrupts FGFR signaling and accounts for insulin resistance in metabolic
syndrome, often encountered in ASD subjects.
Evdokia Anagnostou (University of Toronto) will share her work from a large
Canadian cohort of neurodevelopmental disorders and focus on unpublished
data from new clinical trials targeting E:I balance and synaptic plasticity.
Challenges in cross species translation in this space will be discussed.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 89

WEDNESDAY, JANUARY 29, 2020

Wednesday Morning Panel Sessions

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • AMPHITHEATER

Synaptic Mechanisms Underlying the Pathophysiology of

Autism Spectrum Disorders
Chair: Katherine Roche
Presenters: Katherine Roche, Helen Bateup, Anis Contractor, Gavin Rumbaugh
Autism Spectrum Disorders (ASDs) are a group of prevalent
neurodevelopmental disorders that are characterized by problems with social
engagement and communication, inappropriate repetitive actions, perseverative
behaviors, and a range of associated symptoms, including sensory and motor
abnormalities, intellectual disability, and mood disorders. This panel will bring
together neuroscientists with expertise in studying synapse biology to present
their findings of how synaptic mechanisms contribute to different molecular,
synaptic and circuit phenotypes in models of ASDs. Katherine Roche will
describe work from her lab on rare genetic variants in NMDA receptor subunits
and in neuroligins that are thought to be pathogenic in some cases of intellectual
disability (ID) and ASD. Helen Bateup will present data that explore the neural
basis of ASD traits such as behavioral inflexibility, and restricted, repetitive
patterns of behavior. In particular, she will discuss work showing that synaptic
alterations in the dorsal striatum increase the propensity for motor habit
formation, while impaired dopamine signaling results in inflexible decision-
making strategies. Anis Contractor will discuss how disruptions in GABAergic
signaling during early critical periods affect circuit development and function
in mouse models of autism. In particular he will present work in a mouse model
of Fragile X Syndrome, a neurodevelopmental disorder that causes intellectual
disability and is the largest known cause of autism. Gavin Rumbaugh will
discuss work from his lab on how the ASD risk factor, Syngap1, disrupts both
synaptic function and intrinsic excitability in developing cortical neurons that
contribute to sensory processing.

90 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • CANYON

The Point of Snow Return: Long-Term Effects of

Adolescent Cannabinoid Exposure on Drug Addiction and
Maladaptive Decision Making in Adulthood
Chairs: Jennifer Wenzel, Natalie Zlebnik
Presenters: Jacqueline-Marie Ferland, Natalie Zlebnik, Jibran Khokhar, Christie Fowler
Cannabinoids (CBs) are the most commonly abused drugs among adolescents,
and excessive CB use in this population is associated with the development of
psychiatric conditions, including substance use disorder (SUD). However, how
CB exposure alters brain function to predispose an individual to SUD remains
unclear. This panel will highlight research on the long-term behavioral and
neurobiological effects of adolescent CB exposure, including how CB exposure
affects self-administration of several different drugs of abuse in adulthood.
Dr. Ferland will present recent work exploring the dose-dependent effects of
adolescent exposure to the CB delta-9-tetrahydrocannabinol (THC) on cost/
benefit decision making, stress reactivity, reward sensitivity, cognition, and
impulsivity in adult rats, along with correlated THC-induced neuromolecular
changes. Dr. Zlebnik will discuss how CB exposure in adolescence disrupts the
development of dopamine neurocircuitry and alters cocaine self-administration,
cocaine-mediated anxiety, and cocaine-evoked phasic DA release in adult mice.
Dr. Khokhar will present findings from behavioral and electrophysiological
studies assessing the impact of adolescent THC vapor exposure, either alone
or in combination with alcohol, on instrumental and Pavlovian learning, object
recognition memory, delay discounting, alcohol drinking, and corticostriatal
function in adult rats. Dr. Fowler will discuss recent studies demonstrating long-
term dose- and sex-dependent effects of adolescent nicotine and CB exposure
on nicotine self-administration and relapse-related behaviors, as well as how
mice respond to acute re-exposure to CBs on nicotine intake in adulthood.
Altogether, these presentations provide an overview of our current knowledge
on the lasting effects of CB exposure on developing brain function and behavior
in rodent models, and they may help to identify mechanisms that may render
individuals more susceptible to the reinforcing effects of abused drugs.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 91

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • CHEYENNE

Transgenerational Inheritance of Stress and Drug

Exposure: Effects on Brain, Behavior, and the Epigenome
Chair: Lisa Goldberg
Presenters: Lisa Goldberg, Julie Blendy, Gregg Homanics, Chris Pierce
Paternal exposure to drugs of abuse or stress can produce profound effects
on the physiology and behavior of offspring via epigenetic modifications.
Dr. Goldberg will present on the effect of paternal nicotine exposure on
fear conditioning, hippocampal cholinergic functioning, hippocampal gene
expression and methylation. The findings in collaboration with Dr. Tom
Gould indicate that paternal nicotine exposure resulted in increased fear
learning, decreased cholinergic function, and altered gene expression in
progeny, producing a phenotype similar to symptoms associated with post-
traumatic stress disorder. Dr. Blendy will present her findings regarding the
transgenerational inheritance of paternal stress exposure, and its interaction
with nicotine exposure. Paternal stress exposure produced a protective
phenotype in a sex-specific manner. In the male lineage, grandparent nicotine
exposure abrogated nicotine locomotor sensitization in male and transiently
enhanced nicotine locomotor sensitization in female grandoffspring. Dr.
Homanics will present his work in a rodent paternal preconception chronic
intermittent ethanol exposure paradigm, where they have discovered that male
offspring of ethanol exposed sires have altered sensitivity to several behavioral
effects of ethanol and stress hyporesponsitivity. Mechanistic studies have
revealed that ethanol exposure alters the small noncoding RNA content of
sperm, possibly via RNA transfer from exosomes to sperm. Dr. Pierce will
present his findings that paternal cocaine self-administration hypomethylates
sperm Cdnk1a resulting in a selective increase in the expression of this gene
in the nucleus accumbens of male offspring, which produces blunted cocaine
reinforcement. Together, this panel provides a framework for the behavioral and
neurobiological consequences of paternal drug and stress exposure and offer
insights into the mechanisms of multigenerational epigenetic inheritance.

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • DUNRAVEN/OBSIDIAN

Neuroimaging Applications for Social and Affective

Modulation of Pain
Chair: Vitaly Napadow
Presenters: Vitaly Napadow, Patrick Finan, Robert Edwards
Pain perception is more than nociception. The experience of pain is highly
modifiable by cortical circuitries which can regulate descending inhibitory
and facilitory pathways in the brainstem, as well as sensory, affective, and

92 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

cognitive processing in the brain. Hence, social contexts and affective states
can significantly contribute to the pain experience, providing pathways for
potential therapies to combat chronic pain. In this panel, we will explore
cutting edge human neuroimaging approaches to better understand how social
and affective determinants can modulate pain perception. Presentations will
cover the patient-clinician relationship, which can powerfully shape pain and
placebo responses; the neural basis for positive emotional pain inhibition; and
the role of catastrophizing in neural response to pain. Dr. Napadow will show
that simultaneously recorded (hyperscan) functional MRI in patient-clinician
dyads reveals concordant activation of social mirroring, empathy, and theory-
of-mind circuitries that support therapeutic alliance within the patient-clinician
relationship. Dr. Finan will show that interventions designed to evoke positive
emotions, such as listening to individually tailored music when pain is high,
alter the functional connectivity of corticostriatal circuits reflecting attentional
preference for rewarding over aversive experience. Dr. Edwards will explore
pain catastrophizing, a much-studied mindset which incorporates rumination,
helplessness, and magnification of the threat value of pain and is well known to
upregulate the pain experience. He will discuss recent neuroimaging approaches
exploring the cortical circuitries supporting pain catastrophizing in chronic pain
patients.

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • GALLATIN

The Spectrum of Social Behavior and its Underlying

Mechanisms
Chair: Marco Venniro
Presenters: Marco Venniro, Marijke Achterberg, Alexa Veenema, Sam Golden
Social interaction is an ethologically complex behavior with a spectrum ranging
from social play to aggression. Both forms of interaction can be rewarding for
either humans or laboratory animals. Lately, these behaviors have increasingly
been modeled and incorporated in preclinical animal models to study
underlying neural mechanisms. Based on this, we will present recent findings
exploring the behavioral and neurobiological features of the large spectrum
of social interactions. Marco Venniro (NIDA) will discuss data from a novel
community reinforcement approach rat model, showing the critical role of
central amygdala PKCδ-expressing neurons in inhibition of incubation of
methamphetamine craving after social choice-induced voluntary abstinence.
Marijke Achterberg (Utrecht University) will give an overview of the
neuropharmacology of social play and will show data on individual differences
in social play and how these differences affect adult behavior. Alexa H. Veenema
(Michigan State University) will show data on the role of oxytocin in bed
nucleus of the stria terminalis and in the nucleus accumbens in facilitating
social recognition and social play behavior in sex-specific ways, respectively.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 93

Sam Golden (University of Washington) will present a model of compulsive
aggression seeking and relapse and the role of specific cell-types in controlling
aggression reward. He will also highlight recent advances in computer vision
and machine learning for automated scoring of aggressive behavior. Collectively,
this panel will illustrate the current and future directions of the neuroscience of
social behaviors.

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • GIBBON

Inflammation as a Risk Factor for Psychiatric Illness

Chair: Victoria Risbrough
Presenters: Samantha Friend, Lilly Schwieler, Sophie Erhardt, Margarita Behrens
Converging evidence implicates inflammation as a risk factor for psychiatric
illnesses. Inflammatory factors may serve as biomarkers of illness risk and
inform treatment strategies. This symposium will provide new insights on
both central and peripheral immune contributions to mental illness. We will
discuss clinical and animal data on inflammatory risk factors, their biochemical
consequences, and potential mechanisms for the effects of inflammation
on psychiatric risk. Dr. Friend will discuss the role of immune signaling in
posttraumatic stress disorder (PTSD) and present new preclinical studies
using genetic and viral tools dissecting the role of C-Reactive Protein and
Interleukin-10 in rodent models of PTSD. She will also discuss the potential
for neuronal- and astrocyte-derived exosomes to probe CNS inflammation
in trauma disorders. Dr. Schwieler will discuss the significance of G protein
receptor kinase (GRK)-3 for the induction of psychosis and cognitive
dysfunctions. Recent studies suggest that the GRK3 receptor controls p2x7-
induced secretion of the pro-inflammatory cytokine interleukin (IL)-1β. In
this presentation, Dr. Schwieler will present new data showing that mice with a
targeted deletion of GRK3 display increased hippocampal levels of IL-1β and
induced activity in the kynurenine pathway along with increased synthesis of
kynurenic acid and enhanced dopamine-response as well as aberrant behavior,
such as disrupted prepulse inhibition. Dr. Erhardt will discuss the role of central
and peripheral activity in the kynurenine pathway on suicide risk and bipolar
disorder. This pathway, which is activated by inflammation, may constitute
a causative link between inflammation and psychiatric symptoms, due to
its production of metabolites acting on NMDA receptors. Dr. Behrens will
present data on the long term effects of disruption of the maternal immune
environment on DNA methylation patterns and development of cortical
pyramidal neurons.

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PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • LAKE

Behavioral Correlates of Circuit and Metabolic

Dysfunction in Various Models of Traumatic Brain Injury:
Finding Common Ground
Chair: Akiva Cohen
Presenters: Kaitlin Best, Amber Nolan, Akiva Cohen, Edward Hall
Annually 1.5 million Americans sustain a traumatic brain injury (TBI) from
which 230,000 people are hospitalized and survive, and 50,000 people die.
Assorted traumas cause TBI, including acceleration and impact. Ensuing
pathologies are linked to a range of clinical severities. Though numerous studies
have revealed TBI-induced alterations in cellular, synaptic and metabolic
function in frontolimbic circuits, core pathologies shared across injury models
and severities and their relevance to neurobehavioral prognosis have yet to
be definitively determined. Our panel will compare and contrast maladaptive
neural remodeling and related behavioral deficits observed in multiple models.
Kaitlin Best (CHOP/UPENN) will present findings from a lateral fluid
percussion injury (LFPI) model on the effect of mild TBI on pain sensitivity
and pain-related aversive behaviors, as linked to basolateral amygdala function.
Amber Nolan (UCSF) will present a model of frontal lobe contusion that
produces deficits in reversal learning and alterations in inhibitory circuits in the
orbitofrontal cortex. Akiva Cohen (CHOP/UPENN) will discuss impairments
in a working memory task after mild LFPI and underlying alterations in ventral
hippocampal-medial prefrontal cortex circuit function. Edward Hall (UKy) will
show data on the combination of mechanistically complementary antioxidant
agents to mitigate mitochondrial dysfunction, decrease cortical lesion volume
and improve motor and memory function after moderately severe focal (CCI)
brain injury. This session will couple two seasoned investigators together with
two young investigators new to a WCBR panel to inform the neuroscience
community on the complexity of physiological, biochemical and behavioral
changes observed after TBI. The panel will form a foundation to discuss the
challenges and opportunities to develop therapies for a heterogenous injury
phenotype with a focus on translational mechanisms to improve human
outcomes after brain injury.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 95

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • LAMAR

Navigating the Biology of Schizophrenia: From Genetic

Risk to Novel Treatment Targets
Chair: Thomas Hyde
Presenters: Brady Maher, Thomas Hyde, Elizabeth Tunbridge, Robert Sweet
As Genome Wide Association Studies generated by the Psychiatric Genetics
Consortium have accrued increasingly larger numbers of subjects, the number
of loci associated with significant risk of schizophrenia have correspondingly
increased. Understanding the mechanisms of genetic risk are the first steps
towards understanding the pathobiology of complex behavioral disorders. The
development of novel medications with greater efficacy and fewer side effects
are dependent upon clarity in the mechanisms of risk. In order to translate
clinical genetics into mechanisms of risk, a multiplicity of approaches are
being employed. Brady Maher will present the results of investigations using
human induced pluripotent stem cells differentiated into cortical neurons to
assess molecular and functional changes associated with schizophrenia-derived
polygenic risk scores. Thomas Hyde will present data from postmortem human
brain studies of dentate gyrus on regionally specific signatures of gene expression
associated with specific genetic risk loci in schizophrenia. Elizabeth Tunbridge
will present findings from in depth analyses of CACNA1C, a gene that is well
established as part of the risk architecture of schizophrenia, and also a tantalizing
potential therapeutic target. Finally, Robert Sweet will focus on a molecular
point of convergence, the phosphorylation of Microtubule-associated Protein 2
(MAP2), which is downstream of multiple genes now established by unbiased
methods as schizophrenia risk genes. MAP2 phosphorylation is substantially
altered in schizophrenia and associates with dendritic and proteomic pathology.
This panel will demonstrate the utility of a diversity of approaches in pursuit of a
greater understanding of the pathobiology of schizophrenia, and the promise of
these approaches in identifying new targets for treatment.

PANEL • WEDNESDAY • 7:30 A.M. - 9:30 A.M. • TALUS

Dopamine in Reward and Learning

Chair: David Bortz
Presenters: Briac Halbout, Elizabeth Holly, David Bortz, Kenneth Amaya
The ability to learn to obtain rewards and to adapt such behaviors in the face of
a changing environment is critical for survival and dopamine (DA) is strongly
implicated in these processes. This panel will discuss recent findings describing
the ways in which DA signaling can affect reward learning in goal directed and
pavlovian learning, as well as cognitive flexibility.

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Briac Halbout will describe recent work investigating the contribution of the
mesocorticolimbic system in coordinating discrete reward-seeking and reward-
retrieval behaviors in rats. Dr. Halbout will discuss how reward-paired cues
and expected reward value influence the performance of reward-seeking and
-retrieval responses.
Elizabeth Holly: The dorsomedial striatum (DMS) is a key mediator of goal-
directed (operant) behavior, serving as a critical node integrating sensorimotor,
motivational, and cognitive information to drive motor execution. I will
describe how DMS DA signaling evolves during the acquisition of an operant
task, and how these signals can be locally modulated by striatal interneurons to
accelerate learning.
David Bortz: DA release is necessary for cognitive flexibility tasks. However,
little is known about how circuitry upstream of the midbrain, which regulates
DA release via control of population activity, could affect strategy switching. My
results suggest that activation of the medial septum enhances reversal learning
and set shifting performance via a unique, bidirectional regulation of DA
neuron population activity.
Kenneth Amaya: Appetitive sign-tracking (ST) is a phenomenon involving the
development of a conditioned response to cues that are predictive of reward
in Pavlovian conditioning. Recent reports have indicated that ST is resistant
to nausea-induced outcome devaluation. My present findings suggest that (1)
sign-tracking behavior is, in fact, sensitive to outcome devaluation and (2)
residual sign-tracking behavior does not require nigrostriatal projections.

Wednesday Afternoon Panel Sessions

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • AMPHITHEATER

The Interaction Between Diet and Cognitive Flexibility

Chairs: Laura Corbit, Stephanie Borgland
Presenters: Laura Corbit, Stephanie Borgland, Amy Reichelt, Alain Dagher
Obesity has reached alarming prevalence worldwide. Although many people
attempt to control their weight, most fail over the long-term indicating lack
of flexible control. This session will focus on recent research exploring the
relationship between diet and cognitive flexibility. Dr. Corbit will describe
how an obesogenic diet reduces sensitivity to outcome value, dysregulates
glutamate transmission in corticostriatal circuits, and how restoring glutamate
homeostasis in the striatum can improve behavioural performance. The
orbitofrontal cortex (OFC) receives sensory information about food and
integrates this with expected outcomes. Dr. Borgland will present data
demonstrating that exposure to a palatable diet alters astrocyte modulation
of glutamate homeostasis within the OFC, which influences GABAergic
neurotransmission. She will also present data showing impaired reward

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 97

devaluation in obese rodents and restoration by increasing OFC GABAergic
transmission. In addition to effects on projection neurons, obesity is
increasingly recognized to alter plasticity through effects on extracellular matrix
components called perineuronal nets-structures that encase parvalbumin
interneurons. Dr. Reichelt will describe how modulation of parvalbumin
neuron activity with DREADDs affects memory performance in both control
and obese mice. Finally, Dr. Dagher extends the study of the relationship
between diet and cognition to humans. He will discuss work analyzing cognitive
performance, personality, and MRI derived cortical thickness and connectivity
patterns related to BMI. This data shows patterns of reduced cognitive flexibility
and impulsivity related to higher body weight as well as data suggesting that the
genetic factors that confer vulnerability to obesity are mostly expressed in the
brain, and likely relate to higher cognitive functions such as flexibility and self-
regulation. In sum, this session will provide insight into the complex interplay
between diet and cognition.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • CANYON

AMPA Receptors in Synaptic Plasticity: From Biogenesis

to Potentiation
Chair: Ulli Bayer
Presenters: Ingo Greger, Bernd Fakler, Elva Diaz, Ulli Bayer
Higher brain functions such as learning, memory and cognition are thought
to require the ability of synapses to undergo plastic changes in their strength.
At excitatory synapses, these changes are thought to be largely expressed
by changes in the AMPA-type glutamate receptors (AMPARs). This panel
will discuss recent advances in our understanding of AMPAR structure
and regulation. The panel will start out with detailed discussion of AMPAR
structure and biogenesis, and then move towards the signaling mechanisms
that regulate AMPAR function at the synapse. Ingo Greger (MRC Laboratory
of Molecular Biology, UK) will present cryo-EM structural and functional
experiments elucidating the role of TARP auxiliary subunits in AMPA receptor
synaptic transmission and plasticity. Implications for function and regulation
will be discussed. Bernd Fakler (University of Freiburg, Germany) will describe
analysis of the AMPAR interactome and how specific protein complexes
regulate the biogenesis, transport, and function of the receptor. Elva Diaz
(University of California, Davis) will describe the regulation of excitatory
synapse plasticity and of cognitive function by the AMPAR-associated protein
SynDIG4. Ulli Bayer (University of Colorado Anschutz Medical Campus) will
describe the bi-directional regulation of AMPAR-dependent synaptic strength
by CaMKII, including a novel mechanism that directs the differential response
to the stimulation frequency.

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PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • CHEYENNE

Cells & Circuits Contributing to Opioid Use Disorder

Chairs: Alexander Smith, Michael Stefanik
Presenters: Michael Stefanik, Giuseppe Giannotti, Emmanuel Darcq, Alexander Smith
The U.S. is currently in the midst of an opioid overdose epidemic that
claims more than 115 lives each day. Opioid dependence is characterized
by vulnerability to relapse following protracted abstinence, and relapse
prevention is a primary outcome goal of efforts for novel pharmacotherapeutic
development. All currently approved FDA-approved therapeutics for opioid
use disorder directly target opioid receptors, and thus may serve as replacement
therapies, not necessarily addressing the root cause of the disorder. In this
panel, we will discuss our efforts on understanding the neurobiology critical
for opioid withdrawal and relapse, with a focus on potential for development of
circuit–based therapeutics for prevention of opioid use disorder. First, Michael
Stefanik (North Central College) will present data demonstrating maladaptive
AMPA receptor plasticity in the nucleus accumbens (NAc) that is produced
by extended-access oxycodone self-administration, and underlies incubation
of craving following prolonged abstinence. Next, Giuseppe Giannotti (UC
Denver, Anschutz Medical Campus) will present data optogenetically dissecting
the role of the paraventricular thalamic projections to NAc in mediating opioid
aversion, withdrawal, and reinstatement of heroin seeking. Emmanuel Darcq
(McGill University) will then talk about whole brain functional connectivity
in a mouse model of protracted abstinence from chronic morphine, with a
focus on relation to despair behavior. Finally, Alexander Smith (Icahn School
of Medicine at Mount Sinai) will present translational data on development
of a novel Orexin receptor 1 specific antagonist, and its efficacy in reducing
opioid self-administration, craving, and reinstatement. Together, this session
will highlight recent advances in our understanding of neurobiology of opioid
addiction, and how this may be targeted for development of novel circuit-based
pharmacotherapeutics.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • DUNRAVEN/OBSIDIAN

Some Will Ski Down the ‘Dark Side’: Uncovering Neural

Substrates of Individual Vulnerability to Mood and Anxiety
Disorders
Chair: Marek Schwendt
Presenters: Marek Schwendt, Lori Knackstedt, Jennifer Rainville, Eric Nunes
Pre-existing biological factors contribute to individual vulnerability to
develop stress-induced anxiety and mood disorders. This panel will highlight
recent findings on neurobiological mechanisms of vulnerability/resilience.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 99

Marek Schwendt will present data indicating a critical role for BLA mGlu5
receptors in resilience to long term anxiety after predator scent stress in
male rats. He will provide evidence that upregulation of mGlu5 in this brain
region predicts phenotypic stress resilience, while inhibition of this receptor
population exaggerates contextual fear. Next, Lori Knackstedt will discuss sex
differences in anxiety behaviors in a rodent model of PTSD. She will present
data demonstrating that male and female rats display distinct fear and anxiety
symptoms that persist weeks after a single predator scent exposure. Potential
sex differences in mGlu5 mRNA expression in the amygdala-PFC circuit will
also be discussed. Jennifer Rainville will introduce research showing that
women and men with treatment resistant depression display unique cytokine
profiles when compared to controls or treatment-responsive patients. She
will show how backtranslation of these sex differences into mice reveals that
activation of pro-inflammatory cytokines are sex and depression/stress-type
specific. She will also examine the correlation between specific behaviors
and symptoms with individual cytokine concentrations to identify potential
targets for susceptibility and resilience in males and females. Eric Nunes will
introduce the role of phasic dopamine (DA) activity and release in the VTA
to NAc pathway in stress and depression-related behavior in rodents. He will
discuss how VTA cholinergic receptors, which regulate phasic DA release in the
NAc, also mediate behavioral responses to stress and anxiety in animal models.
Specifically, he will show data supporting the hypothesis that M5 blockade in
the VTA attenuates anhedonic, anxiogenic and depressive-like responses in rat
models.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • GALLATIN

Reward Under a Bad Sign: Neural Mechanisms to Navigate

Motivated Action Under Risky Conditions
Chair: Michael Saddoris
Presenters: Catilin Orsini, Michael McDannald, David Jacobs, Michael Saddoris
In natural settings, animals are tasked with continuously making decisions that
simultaneously weight the prospective gains available (such as food or mates)
while minimizing risk factors like predation or injury. Because risk and reward
probabilities are uncertain in these settings, animals must decide the conditions
under which to seek valuable outcomes under threat. Thus, conflict between
motivated behavior under stochastic risk likely depends on neural circuits
that are able to detect and resolve these conflicts in order to optimally guide
behavior. This symposium will review innovative models of rodent models of
these risk/reward conflicts, providing new insights into motivation, decision
making, punishment and drug dependence. Dr. Caitlin Orsini will discuss
the relationship between food seeking in the face of possible punishment
and drug-seeking behavior and its underlying neurobiological substrates. Dr.

100 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Michael McDannald will examine how threatening cues exert powerful control
over reward, and that ventral pallidum neurons show distinct but overlapping
signals for relative threat and reward critical for these processes. David Jacobs
from Dr. Bita Moghaddam’s lab will present new findings on the potential role
of prefrontal cortical regions (mPFC and OFC) in a chained probabilistic
punishment resistance task in order to assesses how reward motivated action
becomes increasingly resistant to punishment in male and female rats. Finally,
Dr. Michael Saddoris will examine how neural pathways in the prefrontal
cortex, nucleus accumbens and dorsal striatum distinctly contribute to flexible
strategies in continuously risk-updating rodent gambling task. Together, the
panel will provide new perspectives on the neural circuits of emergent decision
networks that may mediate reward/threat conflict.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • GIBBON

Sex-Differences in Chronic Pain State From the Bench to

the Bedside
Chairs: Josee Guindon, Sybil Stacpoole
Presenters: Khalid Benamar, Josee Guindon, Sybil Stacpoole, Vani Selvan
The societal and economic impact of chronic pain is tremendous, accounting
for an estimated $600 billion annually in medical expenses and loss of
work productivity (Gaskin and Richard, 2012). Despite improvement in
our understanding of pain pathways through breakthrough discoveries and
use of translational animal pain models, the scourge of the affliction for
chronic pain patients continues unabated. The current pharmacological
approaches to alleviate pain such as nonsteroidal anti-inflammatory drugs,
opioids, anticonvulsants, antidepressants and cannabinoids offer partial and
unsatisfactory relief. In this symposium, we will bridge preclinical and clinical
studies in regards to chronic pain state related to HIV, chemotherapy, multiple
sclerosis and other unknown etiology. Dr. Benamar will discuss chronic pain in
preclinical studies in HIV-mouse model and sex-specific findings in analgesic
treatments following administration of cannabinoids and anticonvulsants.
Dr. Guindon will emphasize on sex-differences found in analgesic effects of
antidepressants, anticonvulsants and cannabinoids. She will present new
exciting data on the role of sex hormones using her optimized chemotherapy-
induced pain model. Dr. Stacpoole, as a physician expert in chemotherapy-
induced pain and multiple sclerosis in patients, will share her findings about
clinical outcomes and sex-specific differences in treatment options. To conclude
our symposium, Dr. Selvan will share her 25 years of clinical expertise in
patients care in regards to chronic pain in male and female non-cancer, multiple
sclerosis and HIV patients using narcotic (opioids) and non-narcotic therapies
such as antidepressants and anticonvulsants. This symposium will shed the

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 101
lights on the importance of sex-differences in the treatment of chronic pain and
how new preclinical and clinical studies need to take into considerations the
role of sex-hormones in the treatment of chronic pain in patients.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • LAKE

Autism Spectrum Disorder - Bedside to Bench

Chair: Angus Wilfong
Presenters: Angus Wilfong, Anne Anderson, Heather Born, Richard Frye
This panel discussion will review emerging basic and translational science that
has been driven by the vexing clinical challenge of helping children with autism
spectrum disorder and associated comorbidities, particularly epilepsy. These
unmet clinical needs provide research challenges and opportunities in the
laboratory.
Angus Wilfong (Barrow Neurological Institute) will begin with a clinical case
of autism and epilepsy who underwent brain surgery that dramatically resolved
both conditions. Anne Anderson (Baylor College of Medicine) will discuss
two rodent models of epilepsy (Angelman and tuberous sclerosis) that display
features of autism. Heather Born (Baylor) will characterize the social behavioral
deficits seen in these models. Richard Frye (BNI) will review his basic science
work in how mitochondrial dysfunction may underlie features of autism and
epilepsy and how the ketogenic diet is helpful for both conditions.
This session is designed to be interactive, with brief presentations and an
extensive discussion period. Registered audience participants will be allowed
three minutes and a single slide during the discussion.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • LAMAR

There is an Aptamer for That! Nucleic Acid-Based

Chemosensors for Brain Research
Chair: Tod Kippin
Presenters: Kevin Plaxco, Netz Arroyo, Philip Vieira, Karen Scida
Brain function involves myriad interacting chemicals that undergo rapid
concentration fluctuations. Current neurochemistry techniques are challenged
to appropriately monitor brain chemistry in a number of ways. The focus of this
panel is on the electrochemical aptamer-based biosensor (EAB) platform that
is capable of versatile measurements of a wide variety of molecules while also
providing both high temporal resolution and real-time measurements. In brief,
the EAB platform employs electrode surfaces modified with DNA aptamers
that are attached to a redox reporter which together allow concentration-
sensitive changes in current under voltametric interrogation. Kevin Plaxco
(University of California, Santa Barbara) will describe the invention of

102 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

the EAB sensors as a generalizable tool for achieving continuous real-time
monitoring of a variety of analytes, including neurotransmitters, hormones,
and drugs. Next, Netz Arroyo ( John Hopkins Medical School) will describe
strategies for adopting EAB sensors for measurements in vein and in brain
of living subjects with a focus on techniques for probe implantation, drift
correction and prevention of probe degradation. Philip Vieira (California State
University-Dominguez Hills) will describe the application of EAB sensors for
ultra-high precision pharmacokinetic measurements with a focus on individual
differences as well as integration of EAB sensors into closed-loop engineering
approaches to achieve feedback-controlled drug delivery. Lastly, Karen Scida
(Diagnostic Biochips Inc) will discuss incorporation of EAB sensors into
electrophysiological platforms in order to achieve simultaneous electrical and
chemical measurements of brain activity. Overall, the panel will seek to illustrate
the potential of the EAB sensors to advance of our view into brain function
as well as provide translational tools to improve management of clinical
conditions.

PANEL • WEDNESDAY • 4:30 P.M. - 6:30 P.M. • TALUS

Adapting to Change: The Circuitry Underlying Behavioral

Flexibility
Chairs: David Bortz, Anna Radke
Presenters: Anna Radke, David Bortz, Alicia Izquierdo, Zackary Cope
Cognitive flexibility is the ability to shift perspectives and strategies in the face
of changing environmental contingencies, a construct that is key to living an
independent life. Unfortunately, deficits in cognitive flexibility are among the
most pervasive symptoms across psychiatric and neurological disorders. As
such, understanding the circuitry that regulates this cognitive construct is a
major priority in the field of neuroscience and the topic of this panel. Using
fast-scan cyclic voltammetry, Dr. Anna Radke will present data demonstrating
a role for dopamine (DA) release in the nucleus accumbens core in reversal
learning. She found that manipulation of DA neurons specifically influences
perseverative responding during early reversal. Dr. David Bortz will present data
showing a key role for the medial septum (MS), via a direct projection to the
hippocampus, for both reversal learning and set shifting. His results suggest that
activation of the MS enhances reversal learning and set shifting performance via
a unique, bidirectional regulation of midbrain DA neurons. Dr. Alicia Izquierdo
will present data comparing orbitofrontal cortex (OFC) and anterior cingulate
(ACC), together with basolateral amygdala, in flexible reinforcement learning
under uncertainty. Her results suggest highly overlapping, less specialized, roles
for ACC and OFC in learning under uncertainty that point toward a shared
role of both structures in keeping track of outcomes over time. Dr. Zackary
Cope will present data examining a role for locus coeruleus inputs to prelimbic/

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 103
infralimbic cortex in set shifting. He finds a facilitation of performance on
extradimensional shifts following direct activation of this pathway, which results
from more consistent performance of new behaviors during the transition
between old and new rules. Together, these speakers will provide an up-to-
date overview of the breadth of different, but interconnected, neural circuits
controlling flexible behavior.

THURSDAY, JANUARY 30, 2020

Thursday Morning Panel Sessions

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • AMPHITHEATER

Spatiotemporally-Specific Patterns of Dopamine Release

Shape Action Selection
Chair: Daniel Covey
Presenters: Christopher Howard, Nick Hollon, Anne Collins, Daniel Covey
Brain dopamine (DA) function controls goal-directed action and its
dysfunction is implicated in numerous neuropsychiatric and neurodegenerative
disorders. But how region- and temporally-specific patterns of DA release in
the striatum differentially shape action selection remains poorly understood.
Our panel will discuss cellular and circuit-level mechanisms that control goal-
directed actions by modulating DA release dynamics across the striatum.
Chris Howard and Nick Hollon will first discuss findings on the role of
nigrostriatal DA signaling in instrumental behavior. Chris Howard will present
recent work investigating how neurochemically distinct subregions of the
dorsal striatum (DS) known as patches (or striosomes) influence striatal DA
release and habit formation through inhibitory projections onto midbrain DA
cell bodies. Nick will then show that self-initiated goal-directed action also
suppresses DA release in the DS according to the action-outcome contingency,
even when the outcome of this action is direct stimulation of midbrain DA cell
bodies. Their work provides fundamental insight into how nigrostriatal DA
pathways guide movement and behavioral sequences.
Annie Collins and Dan Covey will then present recent work showing that
distinct neuromodulatory networks differentially influence DA release in the
nucleus accumbens (NAc) to shape reward seeking. Annie will discuss how
cholinergic interneurons function as a suppressatory gate on reward seeking
by locally inhibiting terminal DA release in the NAc. Dan will then close the
session by showing that NAc DA release differentially signals past and future
reward cost during motivated reward seeking and chronic pharmacological
enhancement of endocannabinoid (eCB) signaling stably facilities DA function
and motivation.

104 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • CANYON

Advances in Cell-Type Specific Detection and

Manipulation of Neurotransmitters
Chair: David Root
Presenters: Jason Dong, Jonathan Marvin, Dillon McGovern, Michael Tadross
Calcium imaging and channelrhodopsin-assisted electrophysiological methods
have greatly advanced understanding of the neuronal activity patterns of
genetically-defined neurons during motivated behavior. However, the cell-type
specific neurochemical mechanisms that underlie neuronal activity patterns
during motivated behavior are unclear. Recently, several neurotransmitter-
specific sensors have been engineered with cell-type specific precision. In
addition, the recently-engineered DART technology allows for cell-type
specific pharmacological manipulation. This panel will present the latest
neurotechnology to detect and manipulate specific neurotransmitters as well
as present new research on their use during motivated behaviors. Jason Dong,
a graduate student in Dr. Lin Tian’ s lab will describe the engineering and
use of serotonin sensors during motivated behavior and to enable real-time
pharmacology for psychedelic discovery. Dr. Jonathan Marvin, Senior Scientist
at Janelia Farms, will discuss the protein engineering and development of
sensors for glutamate, GABA, ATP, and acetylcholine. Dillon McGovern,
graduate student in the Root lab, will present his research recording glutamate
and GABA binding on ventral tegmental area glutamate neurons that identifies
novel neurochemical mechanisms underlying how these specific neurons signal
reward, aversion, and learned predictors of these outcomes. Finally, Dr. Michael
Tadross will discuss the engineering and use of DART in multiple cell-type
specific populations to regulate behavior under motivated and pathological
conditions. Together, this session will demonstrate the utility of a fast-growing
toolbox of sensors for chemical transmission that is well poised to permit
direct functional analysis of how the spatiotemporal coding of chemical input
signaling mediates the plasticity and function of brain circuits.

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • CHEYENNE

Neuronal Ensembles and Engrams in Appetitive and

Aversive Behaviors
Chair: Bruce Hope
Presenters: Denise Cai, Leslie Whitaker, Melissa Malvaez, Rajtarun Madangopal
Learned associations between cues and outcomes guide both appetitive and
aversive behaviors. Learning induces highly specific long-lasting changes
(engrams) in sparsely distributed patterns of neurons (neuronal ensembles)
that encode highly specific learned associations. Identifying the specific neural

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 105
elements that mediate the formation and maintenance of these engrams
and ensembles will allow us to understand and perhaps ameliorate learning-
related disorders such as substance use disorders and PTSD. Bruce Hope
will introduce a panel describing recent work using the latest chemogenetic
and optogenetic methods to manipulate ensembles, and calcium imaging
and electrophysiological methods to identify and characterize functional
alterations within neuronal ensembles that encode appetitive and aversive
learned associations. Denise Cai will discuss how enhancing the valence of a
memory leads to increased retrospective linking through overlapping neuronal
ensembles shared by two memories that link a predictive cue with the outcome.
Leslie Whitaker will present her results showing electrophysiological and
molecular alterations that comprise the engram in PFC neuronal ensembles
that encode drug-based associative learning. Melissa Malvaez will present
data demonstrating the doubly dissociable function of lateral and medial
orbitofrontal cortex projections to the basolateral amygdala (BLA) in
reward value encoding and retrieval, respectively, as well as the BLA output
neurons responsible for using this information to guide adaptive reward
pursuit decisions. Rajtarun Madangopal will present ongoing work aimed
at longitudinal monitoring of neural populations in vivo in rats during
unrestrained operant behaviors. He will also discuss new approaches to
permanently label these populations in an activity-dependent manner using
CaMPARI for ex vivo analysis of cellular and molecular alterations.

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • DUNRAVEN/OBSIDIAN

Après Concussion: Addiction-Related Sequelae of

Traumatic Brain Injury
Chair: Christopher Olsen
Presenters: Alana Conti, Christopher Olsen, Zachary Weil, David Pennington
Traumatic brain injury (TBI) and substance abuse are highly comorbid
diseases. This panel will explore behavioral and mechanistic interactions
between traumatic brain injury (TBI) and substance abuse in rodents and
humans. Alana Conti (Wayne State University School of Medicine and the
John D. Dingell VA Medical Center) will describe the influence of experimental
traumatic brain injury combined with opioid exposure (as a model of post-
injury pain relief) on oxidative stress and inflammatory outcomes, as they
relate to behavioral responding in pain and drug preference assessments. Chris
Olsen (Medical College of Wisconsin) will present data demonstrating elevated
oxycodone seeking in rats exposed to mild TBI, and neuroimaging correlates
of combined injury and opioid exposure. Zachary Weil (West Virginia
University School of Medicine) will present data on the neuroinflammatory
and neuroendocrine links between early TBI and alcohol-related behaviors
later in life. David Pennington (University of California San Francisco and San

106 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Francisco Veterans Affairs Health Care System) will present data on cognitive
remediation (Approach Bias Modification) and N-acetylcysteine treatment for
improving cognitive function in veterans with comorbid alcohol use disorder
and traumatic brain injury.

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • GALLATIN

Opioid Modulation of Striatal Circuitry Drives Diverse

Behavioral Adaptions
Chair: William Birdsong
Presenters: Sweta Adhikary, Tracy Fetterly, Aya Matsui, Nicolas Massaly
In this panel we will investigate mechanisms of opioid modulation of inputs to
and outputs from the dorsal striatum and nucleus accumbens. In particular this
panel of young investigators will discuss how the opioid system can interact
with other neuromodulatory systems to affect behavior in the context of
food and alcohol consumption and inflammatory pain. First, Sweta Adhikary
(Oregon Health & Science University) will discuss how mu opioid receptor
activation regulates the release of adenosine at striatal glutamate synapses and
how chronic opioid treatment alters striatal micro-circuitry by modulating
adenosine’s inhibitory tone at both opioid sensitive and insensitive synapses.
Tracy Fetterly (University of Michigan) will be discussing the mechanistic
actions of insulin on excitatory transmission in the nucleus accumbens
(NAc). More specifically, how insulin receptor activation results in decreased
presynaptic glutamate release in the NAc via an opioid-receptor mediated
mechanism. Furthermore, effects of obesity on the actions of insulin in the
NAc will be investigated. Aya Matsui (National Institute on Alcohol Abuse
and Alcoholism) will present work investigating the role of opioid receptors
in modulating inhibitory transmission from the NAc to the ventral pallidum
and how endogenous opioids act in this circuit to regulate alcohol intake.
Finally, Nicolas Massaly (Washington University, St. Louis) will discuss how
inflammatory pain recruits the dynorphin-kappa opioid system in the nucleus
accumbens to dampen animal’s motivation for sucrose reward and increase
aversive behavior, a hallmark for negative affective states.
Altogether this panel will bring new insights and discuss how the striatal opioid
systems, in healthy and pain conditions, regulate food and alcohol intake.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 107
PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • GIBBON

A Role for Glia in Neuropsychiatric Disorders

Chair: Michelle Olsen
Presenters: Michelle Olsen, Harry Pantazopoulos, Mikhail Pletnikov, Robert McCullumsmith
Central nervous system glia are key players in healthy central nervous system
functioning. A sufficient body of literature now implicates dysfunction of
these cells in major depressive disorder, chronic stress, major depression and
neurodevelopmental/neuropsychiatric disorders. The current panel proposal
focuses on astrocyte and oligodendrocyte dysfunction in neurodevelopmental
and neuropsychiatric illness across pre-clinical animal and iPSC model systems
as well as human postmortem studies models.
Dr. Olsen will discuss altered astrocyte function in the neurodevelopmental/
neuropsychiatric disorder Rett syndrome. Her studies indicate that MeCP2,
the transcriptional regulator disrupted in Rett has unique astrocyte molecular
targets, including the astrocytic protein Kir4.1. Kir4.1 is a glial specific K+
channel which mediates extracellular K+ homeostasis, a critical protein for
regulating extracellular K+ dynamics following neural activity.
Dr. Pantazopoulos will discuss evidence from postmortem human studies,
pointing to a role for astrocytes and oligodendrocyte precursors in the
pathophysiology of major psychoses. Her studies show that interactions
between glial cells, neurons and extracellular matrix are disrupted in
schizophrenia and bipolar disorders, potentially impacting synaptic functions.
Dr. Pletnikov will present his recent studies of potential contribution of neuron-
astrocyte metabolic coupling to neuronal circuit maturation and cognitive
function in a time and brain region-dependent manner. He will discuss data
from his lab and others indicating a role for abnormal astrocyte support
of neuronal activity could lead to neurobehavioral and cognitive changes
consistent with aspects of major psychiatric disorder.
Robert McCullumsmith will discuss the bioenergetic deficits found in iPSC
cells derived from postmortem schizophrenic patient brain tissue. His studies
demonstrate a central role in disrupted glycolysis in neurodevelopment.

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • LAKE

Schizophrenia: Different Phenotypes/Different Brain

Systems
Chair: Matthias Kirschner
Presenters: Neil Cashman, George Foussias, Bratislav Misic, Matthias Kirschner
This symposium is based on the theory that schizophrenia is a progressive
early-onset neurodegenerative disease whose expression is shaped by the brain
connectome. This model harks back to Kraepelin’s conception of Dementia

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Praecox: a degenerative disease affecting multiple spheres of cognitive and
emotional function. We will review clinical heterogeneity in schizophrenia at
from the standpoint of cognitive function, genetics, and brain imaging.
We will introduce the idea of schizophrenia as a neurodegenerative (maybe even
a prion) disease! The speakers will provide new information on phenotypic
variability in schizophrenia.
Neil Cashman will show that DISC1 co-aggregation with TDP-43 has
been found to impair activity-related, dendritic protein translation in
frontotemporal dementia (FTD), and may contribute to psychotic features
of this neurodegenerative disorder (Endo et al, Biol Psych 2018). The DISC1
interactome includes proteins relevant to neurodegeneration that misfold
and propagate in a prion-like fashion. It is possible that DISC1 misfolding,
aggregation, and co-aggregation could participate in neurodegeneration as well
as schizophrenia.
George Foussias (Behavioural phenotypes of motivation deficits in
schizophrenia) will address the motivational deficits. His innovative approach
has uncovered distinct phenotypes of reward-based and intrinsic motivation
deficits in schizophrenia.
Bratislav Misic (Spatial patterning of tissue volume loss in schizophrenia reflects
brain network architecture) will review concepts of network neuroscience, and
show that patterns of brain atrophy in large cohorts of schizophrenia patients
are consistent with a propagating process. He will show that specific brain
networks are vulnerable to the disease.
Matthias Kirschner (Clinical-anatomical phenotypes of schizophrenia)
will show that multivariate methods can extract pehenotypic patterns from
combined clinical and imaging datasets.

PANEL • THURSDAY • 7:30 A.M. - 9:30 A.M. • LAMAR

A Yardsale of Migraine and Headache Animal Models: New

Models and New Developments in Established Ones
Chair: Serapio Baca
Presenters: Amynah Pradhan, Guido Faas, Maggie Waung, Michael Morgan
Migraine and headache are complex neurological disorders that involve a
dizzying number of brain and vascular networks. Despite recent advancements,
there is presently no cure for migraine and many people with migraine
and headache fail to find relief from any current medications. Nonetheless,
improvements in understanding migraine and headache pathophysiology have
arisen from the use of a number of different animal models that capture a subset
of the defining features of the disorder. Or, they have arisen from animal models
generated from the known genetic contributions to the disorder. This panel
will highlight new developments in established models while also featuring
recent research in an invertebrate system. Serapio Baca will provide a brief

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 109
overview of the systems and their utility in migraine and headache research.
Amynah Pradhan will discuss her timely work on the overlapping mechanisms
between opioid-induced hyperalgesia and chronic migraine. Guido Faas will
discuss recent technological innovations for the long-term monitoring of
cortical spreading depression (CSD) and blood flow in mice. Maggie Waung
will discuss her recent work demonstrating that silencing peri-aqueductal
grey (PAG) neurons that project to the ventral tegmental area (VTA) relieves
headache pain. Last, Michael Morgan will provide molecular and cellular
insights on the cholinergic and GABAergic consequences in c. elegans that
come from a gain of function mutation found in humans in familial hemiplegic
migraine type 1 (FHM1). Collectively these panelists employ a number of
behavioral, electrophysiological, optogenetic, and molecular assays in different
models to try to understand processes that are relevant to the understanding
and treatment of migraine and headache.

Thursday Afternoon Panel Sessions

PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • AMPHITHEATER

Big Sky High: Mechanisms of Endocannabinoid System

Control of Brain Function and Nociception
Chair: Carl Lupica
Presenters: Carl Lupica, Zsolt Lenkei, Aron Lichtman, Daniel Morgan
Scientific knowledge of the roles for the endogenous cannabinoid (eCB) system
in regulating multiple physiological and behavioral processes is expanding
at a rapid pace. However, many questions remain as to the mechanisms
through which eCBs regulate the physiological and behavioral processes. The
answers to these questions are important because they will help determine
the therapeutic utility of manipulating the endocannabinoid system in the
treatment of neurodegenerative diseases and psychiatric disorders. In this panel
we present studies designed to answer both fundamental questions regarding
the mechanisms in which the eCB system regulates brain function, as well as
how manipulating this system can impact nociceptive behavior associated with
cancer treatment. Our first speaker, Carl Lupica (NIDA-IRP), will present data
addressing the long-standing problem of how eCBs are released to alter synaptic
function in the CNS. He will provide evidence to show that eCBs are found in
non-synaptic extracellular vesicles (EVs), and that disruption of the release of
EVs can alter effects of ECBs at central synapses. Zsolt Lenkei (INSERM) will
discuss the use of ultrafast functional ultrasound (f US) imaging to localize with
high resolution changes in regional brain connectivity caused by cannabinoid
receptor activation. Aron Lichtman (Virginia Commonwealth U.) will discuss
research examining the use of inhibitors of enzymes of eCB synthesis to
ameliorate nociceptive behavior in a mouse model of chemotherapy-induced

110 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

peripheral neuropathy. Finally, Daniel Morgan (Penn State U.) will talk about
sex differences in responding to cannabinoid agonists in acute and chronic pain
associated with cancer treatment.

PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • CANYON

Kappa Opioid Receptors: The Multi-Headed Gatekeepers

of the Nucleus Accumbens and Motivation
Chair: Jessica Barson
Presenters: Jessica Barson, Anushree Karkhanis, Hugo Tejeda, Elena Chartoff
The kappa opioid receptor (KOR) and its cognate ligand, dynorphin, have
canonically been understood to produce negative affective states, via actions
in the limbic system. In the nucleus accumbens, KORs are believed to induce
these states, in part, by suppressing dopamine release. This panel will describe
new research demonstrating that the relationship between accumbal KORs
and negative affect is far more multifaceted than originally believed. Jessica
Barson will present evidence that behavioral effects of KOR activation in the
accumbens shell depend on its rostro-caudal location. She will describe how
injection of a KOR agonist leads to opposite effects on anxiety-like behavior
and also ethanol drinking when made in the rostral vs. caudal shell. Anushree
Karkhanis will show that KOR control of dopamine release in the nucleus
accumbens is regionally distinct along the rostro-caudal axis following stress
and ethanol exposure. She will discuss how these anatomically-dependent
effects of KORs could mediate the effects of dynorphin on affective states and
motivation. Hugo Tejeda will describe how stress promotes negative affect
via mechanisms that enhance accumbens D1 medium spiny neuron activity,
thus promoting dynorphin release and subsequently activating KORs. He
will discuss how stress-induced dynorphin/KOR signaling may limit nucleus
accumbens cell assemblies that control reward-seeking behavior and adaptive
responses to cope with or avoid threats. Elena Chartoff will describe how KOR
activation has been shown in males to suppress accumbal dopamine release
and trigger depressive- and anxiety-like behavior. She will present evidence in
females that shows these effects of KOR activation are blunted compared to
males, indicating sex differences in the neural circuits necessary for negative
affective states. These presentations will highlight the diverse influences that
determine the neurochemical and behavioral outcomes of KOR activation in
the nucleus accumbens.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 111
PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • CHEYENNE

DNA Structure and Function – at the Nexus Between

Environmental and Genetic Risk for Neuropsychiatric
Disorders
Chair: Amelia Gallitano
Presenters: Amelia Gallitano, Cathy Barr, Madabhushi Ram, Robert McCullumsmith
Recent genome-wide association studies (GWAS) have identified hundreds
of genomic loci associated with risk for neuropsychiatric disorders. Yet, the
molecular alterations in these regions that increase psychiatric illness risk, and
the genes affected by these variations, remain unknown. Moreover, genetics
determine only 50 – 70% of psychiatric illnesses susceptibility, implicating
environment in the remainder. Thus, the next major challenges in psychiatry
are to determine how variations affect the function of genes in these regions,
and how environment impacts the genome to alter these processes. The
panel will address these questions through four approaches. Dr. Gallitano
(University of Arizona) will report novel genes activated in an environmentally
responsive biological pathway influencing memory, behavior, and synaptic
plasticity. This pathway includes numerous genes that map to the Psychiatric
Genomics Consortium (PGC) GWAS loci for schizophrenia and depression.
Dr. Barr (University of Toronto) will report on work aimed to identify the
impact of genetic variants on neural cell function by CRISPR/Cas9 genome
editing experiments that alters genomic regulatory regions associated with
schizophrenia, major depressive disorder, and neurodevelopmental disorders.
Dr. Madabhushi (University of Texas Southwestern Medical Center) will
present work detailing how transcriptional programs that underlie the
development of adaptive behaviors, including long-lasting memories, are
regulated through the formation and repair of DNA breaks at specific genomic
loci, and their implications for neurological disorders. Dr. McCullumsmith
(University of Toledo) will report on an environmental model of loss,
employing RNAseq, shotgun proteomics, and kinomics approaches to identify
the molecular changes that occur in the brain in response to loss following
transition from an enriched, to a deprived, environment. The panel will
conclude with discussion and questions.

112 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • DUNRAVEN/OBSIDIAN

Sex Differences in Neurodevelopmental Abnormalities

Arising From Early Life Insults
Chairs: Debra Bangasser, Jared Young
Presenters: Lauren Ellman, Jared Young, Jennifer Honeycutt, Debra Bangasser
The search for novel treatments for psychiatric disorders is hampered due
in-part to an incomplete understanding of neural abnormalities of patients.
Increasing evidence points toward neurodevelopmental processes being affected
that underlie the altered neurobiology observed in adults. Early life insults, such
as stress and immune disruptions, drive changes in brain development that
increase odds-risk for a psychiatric diagnosis. Importantly, such insults affect
males and females differently, likely contributing to sex differences in psychiatric
illnesses. This panel will present data from humans and animal models revealing
sex differences in neurodevelopmental abnormalities that arise from early life
insults. Dr. Ellman will present longitudinal research revealing that exposure to
maternal inflammation during gestation elevates depression scores in adolescent
offspring in a sex-specific manner. Dr. Young will present research on how
altering photoperiod lengths on mice dams, an early-life gestational stressor,
results in adult offspring with sex-specific alterations in psychiatric-relevant
behaviors, including stress hormones, neuroinflammation, and depressive-
like behaviors. Data will be presented on mice with genetic abnormalities
that display an altered response to this early-life stressor. Dr. Honeycutt will
detail how maternal separation in rats leads to earlier maturation of basolateral
amygdala afferents into the prefrontal cortex; a finding seen in both sexes, but
that occurs earlier in females. Resting state functional connectivity measures
further show lasting alterations in corticolimbic connectivity in females, who
appear uniquely impacted by caregiver deprivation. Finally, Dr. Bangasser will
detail how exposure of rat pups to a limited resource environment can actually
result in sex-specific stress inoculation: promoting resilience of adult males
to impulsivity and drug self-administration, while inducing sex differences in
neuroepigenetic processes.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 113
PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • GALLATIN

Identifying Neurobiological Substrates of Functional

Decline to Help Develop Brain-Interventional Approaches
in Normal and Pathological Aging
Chair: Natalie Ebner
Presenters: Mara Mather, Nathan Spreng, Jennifer Bizon, Natalie Ebner
Aging is associated with functional decline, with deficits exacerbated in
pathological aging. Neuroimaging allows identification of neurobiological
substrates of this age- and pathology-related decline and provides brain-
interventional opportunities for functional enhancement. Panel experts will
present advances from animal and human aging research, integrating innovative
neuroimaging, biomarker, and neurophysiological methodologies. Dr. Mather
will show that while ‘hot spots’ of high excitation are maintained in aging, the
locus coeruleus is less effective at amplifying frontoparietal attention network
activity, reducing older adults’ ability to hone-in on what really matters under
arousal. She will present results that locus coeruleus volume predicts conversion
to Alzheimer’s disease. Dr. Spreng will present work integrating cerebrospinal
fluid biomarkers, multi-modal neuroimaging, and genomic data to triangulate
cell-type specific degeneration of human cholinergic basal forebrain neurons,
involved in memory formation, in vivo at stages of Alzheimer’s disease
preceding cognitive impairment. Dr. Bizon will show that vagus nerve
stimulation (VNS) enhances attentional set shifting in aged rodents. She will
present data that VNS can restore excitatory/inhibitory dysregulation in aging
and will discuss pharmacological and optogenetic methods to determine the
role of noradrenergic or cholinergic modulation in VNS-mediated cognitive
enhancement. Dr. Ebner will present neurofeedback training data using
innovative real-time functional magnetic resonance imaging suggesting that
both healthy older adults and Parkinson’s disease patients can obtain volitional
control over brain activity. She will discuss behavioral benefits on selective
attention associated with neurofeedback success. The panel will conclude with
a brief discussion integrating the findings in the context of current frontiers and
translational impact in research on healthy aging and aging-related disease.

114 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • GIBBON

Novel Models for Studying Stress Influence on Alcohol or

Substance Use Disorder
Chair: Jayme McReynolds
Presenters: Jayme McReynolds, Jessica Loweth, Daniel Manvich, Jeffrey Tasker
Addiction involves interactions among several factors, including stress, that
promote drug and alcohol use. However, the involvement of stress in addiction
is complex and still poorly understood. This is due in part to the lack of newer
behavioral models to examine the various roles for stress in different aspects
of addiction. Considering NIDA’s request for information on animal models
of drug addiction, this panel will highlight novel behavioral models being
used to study the influence of stress on drug and alcohol use and seeking.
Jayme McReynolds (Marquette University) will discuss how repeated daily
stress at the time of drug use can induce an escalation of cocaine intake
and increase susceptibility for reinstatement and highlight the involvement
of endocannabinoids in these effects. Jessica Loweth (Rowan University
School of Osteopathic Medicine) will present data on the effects of chronic
stress exposure during early withdrawal on cue-induced cocaine seeking
behavior in adult male and female rats, including the influence of the estrous
cycle. The effects of cocaine and chronic stress exposure on glutamatergic
signaling pathways in the nucleus accumbens and basolateral amygdala will
also be discussed. Dan Manvich (Rowan University School of Osteopathic
Medicine) will present data using a unique model of psychosocial stress-
induced cocaine seeking in rats, where the magnitude of drug-seeking behavior
is positively correlated with an active, rather than passive, stress-coping
phenotype. Preliminary findings from brain activation mapping studies during
psychosocial stress-induced cocaine seeking will also be presented. Jeff Tasker
(Tulane University) will present data using a model of escalation of alcohol
consumption following predator odor traumatic stress, where traumatic stress
suppresses the acute inhibitory synaptic response to alcohol mediated by
parvalbumin interneuron inputs to principal neurons of the basolateral nucleus
of the amygdala.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 115
PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • LAKE

Dynamic Neural Encoding of Real-Time Behavioral State

Changes in Response to Fear- and Aversion-Inciting
Stimuli
Chair: Lindsay Halladay
Presenters: Jose Rodriguez-Romaguera, Lindsay Halladay, Jonathan Fadok, Robert
Rozeske
Appropriate defensive response selection to ensure survival involves a
coordinated effort from neural regions associated with both innate and learned
fear responding. This panel focuses on dynamic neural encoding of real-time
behavioral changes in response to potentially aversive outcomes. Speaker
presentations reflect the progression of an organism initially responding to
aversive stimuli, then forming an association between stimulus and aversive
outcome, selecting an appropriate defensive response, and finally, rapidly
discriminating aversive vs safe contexts. Jose Rodriguez-Romaguera (UNC
Chapel Hill) used single-cell calcium imaging in freely-moving animals to
identify a subpopulation of neurons in the bed nucleus of the stria terminalis
(BNST) that modulates rapid changes in physiological arousal during exposure
to arousal-inducing stimuli and anxiogenic environments. Lindsay Halladay
(Santa Clara University) recorded single units in BNST during cued fear
learning and characterized two discrete populations of neurons there: phasic
units exhibit robust firing rate changes only during initial cued fear learning and
predict subsequent freezing expression, while ramping units exhibit gradual
firing rate changes that correlate with fear expression during learning. Jonathan
Fadok (Tulane University) examined discrete suites of defense responses
elicited by threat imminence. He used cell type-specific perturbations, neuronal
recordings, and neuroanatomical tracing to characterize global brain networks
mediating the selection and intensity of defensive responses. Finally, Rob
Rozeske (McGill University) combined in vivo calcium imaging with a fear
conditioning task that permits rapid context ‘teleportation’. His results indicate
that hippocampal region CA1 contains subpopulations of cells that are activated
during transitions into a safe or dangerous context. Together these findings
highlight the complex and diverse neural mechanisms underlying the drive to
survive.

116 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

PANEL • THURSDAY • 4:30 P.M. - 6:30 P.M. • LAMAR

Regulation of Excitability: From Channels to Diseases

Chairs: Terunaga Nakagawa, Kasper Hansen
Presenters: Kasper Hansen, John Gray, Tija Jacob, Terunaga Nakagawa
Dysregulation of synaptic transmission is implicated in disease etiologies of
many neurological and psychiatric disorders. To develop therapeutic agents
that mitigate the aberrant regulation in disease states, it is critical to reveal
signaling mechanisms of postsynaptic neurotransmitter receptors. With
recent advances in proteomics and structural elucidation of the members of
NMDA, AMPA, and GABA-A receptors, investigations into their functional
modulation are undertaken at an unprecedented precision. In this panel we
will focus our discussion on novel signaling pathways and mechanisms that
can control excitability via these channels. We will start with introducing
new mechanisms on NMDA receptor functional regulation. Dr. Hansen
will discuss pharmacological regulation of synaptic transmission in distinct
neuronal populations by subtype-specific NMDA receptor glycine site
agonists. Dr. Gray will present implications on synaptic physiology mediated
by regulation of the NMDA receptor co-agonist D-serine, and discuss its
relation to psychiatric disorders. Dysfunction of excitatory synapses occurs in
benzodiazepine treatment, but the molecular bases remain elusive. Dr. Jacob
will discuss molecular pathways that control synaptic adaptation induced
by benzodiazepine tolerance through the action of GABA-A receptors. In
AMPA receptors, gating and trafficking is controlled extensively by its auxiliary
subunits. Dr. Nakagawa will discuss mechanistic insights on AMPA receptor
regulation by auxiliary subunits obtained by cryo-EM and implications on
synaptic transmission. This panel will provide a comprehensive discussion
on novel aspects of synaptic signaling, thereby providing up-to-date and
new perspectives on neurotransmitter receptor from structure-function to
physiology.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 117
 Poster Abstracts
SUNDAY, JANUARY 26, 2020 • 3:30 P.M. - 4:30 P.M. • JEFFERSON/MADISON

S1. Hypothalamic POMC-Expressing Neurons are

Activated by Low-Dose Ethanol
Lauren Hood*, Erin Nagy, M. Foster Olive
Hypothalamic neurons that express proopiomelanocortin (POMC) are
important for regulating metabolism and experiencing satiety. The POMC
peptide is also a precursor for endogenous opioids such as beta-endorphin,
which are implicated in driving addiction and alcoholism. Increased endorphin
levels are found in the nucleus accumbens, amygdala, and hypothalamus of
rodents after both acute and chronic ethanol exposure. However, it remains
unclear how ethanol acts on various endogenous opioid-containing circuits
in the brain. The current study investigated the effects of voluntary ethanol
intake on POMC neuron activity in the arcuate nucleus of the hypothalamus.
Male and female transgenic mice expressing enhanced GFP (eGFP) under
the POMC promoter were given free access to 20% ethanol for two hours
during the dark phase of their light cycle in a paradigm titled drinking-in-the-
dark (DID). After 3 consecutive days of habituation to this procedure, mice
were given short access (20 min) to either 20% ethanol, 0.25% saccharin, or
water. One hour after the 20-min access period, mice underwent transcardial
perfusion, blood sampling for assessment of blood alcohol levels, and brain
extraction for immunohistochemical analysis of c-fos expression. Ethanol
intake and blood ethanol levels in males were 0.6±0.2 g/kg and 10±5 mM,
respectively, and in females were 0.6±0.1 g/kg and 7±3 mM, respectively. The
percentages of c-fos expressing POMC neurons were 19.2±2.5% in ethanol-
consuming males and 17.3±4.3% in ethanol consuming females, which were
significantly greater than those observed in saccharin or water consuming mice.
These data suggest a subset of POMC-expressing neurons in the arcuate nucleus
are a target of low-dose ethanol when voluntarily consumed.

118 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

S2. An Electrochemical Aptamer-Based (E-AB) Biosensor
Platform for Real-Time, High Precision Pharmacokinetic
and Pharmacodynamic Measurements Within the Brain
Julian Gerson*, Philippe Ducharme, Kyle Ploense, Netz Arroyo, Kevin Plaxco, Tod
Kippin
The brain is an incredibly complex signaling organ, simultaneously coordinating
the release and detection of multiple chemicals that can exert their impact as
rapidly as on the order of tens of milliseconds. As neuroscientists, our ability to
understand how the brain works is inherently linked to our ability to detect and
manipulate these signals in order to understand their endogenous effects. As
such, we are only as strong as the tools available to us. Current techniques are
challenged to resolve more than a small number of these signaling molecules,
or exogenously administered drugs, on physiologically appropriate timescales.
In response to this, our group has developed a novel platform, electrochemical
aptamer based (E-AB) biosensors, capable of detecting physiologically
relevant ranges of exogenously administered pharmacological agents, as well
as endogenously present targets of interest. Here we present three novel
implementations of this platform. We have developed and implemented an in
brain E-AB sensor capable of detecting serotonin (5-HT) with high specificity
in awake, ambulatory subjects. 5-HT is an endogenous neurotransmitter
that has critical participation in a wide range brain functions, such as arousal,
motivation, learning, and equally has been implicated in disorders, such as
depression, anxiety, schizophrenia, addiction, and insomnia. In addition,
we have developed and implemented another in brain E-AB sensor for the
detection of cocaine levels in the brain, an exogenous psychoactive compound
known to strongly influence 5-HT signaling in the brain. Together, these sensors
could be used to give us further insight into the impact of cocaine on 5-HT
circuitry, as well as the role of 5-HT in the development and persistence of
psychostimulant addiction. Lastly, we have adapted an E-AB sensor specific for
Vancomycin in the circulatory system (previously reported by our group), for
in brain detection. Here we present simultaneous measurements of Vancomycin
levels in both the circulatory system as well as the brain at high time resolution
(11 seconds) in order to explore drug specific blood brain barrier kinetics.

S3. Perineuronal Net Removal Prior to but Not Following

Retrieval Attenuates Cue-Induced Reinstatement in
Cocaine Self-Administering Rats
Jereme Wingert*, John Harkness, Angela Gonzalez, Ryan Todd, Barbara Sorg
Repeated cocaine exposure can lead to the formation of persistent drug
memories that contribute to drug seeking behavior. The medial prefrontal
cortex (mPFC) is instrumental in cocaine-induced drug-seeking behavior

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 119
and memory. Here we investigated the impact of removal of perineuronal nets
(PNNs) with chondroitinase ABC (Ch-ABC) on cocaine-associated memory
reconsolidation. First, we showed that Ch-ABC rapidly degraded PNNs in vivo
within 1 hour of injection, suggesting that it may be effective at attenuating
reinstatement when injected post reactivation. To explore pre- and post-
reactivation Ch-ABC treatment on behavior, rats were trained to self-administer
cocaine on a fixed ratio 1 (FR1) schedule of reinforcement for 10 days. One
cohort received intracranial Ch-ABC 3 days prior to the reactivation session
(pre-reactivation) on the last day of training, while the other received Ch-ABC
90 min after reactivation (post-reactivation). Rats were given a 30 min memory
reactivation session using either an FR1 or a novel variable ratio 5 (VR5)
schedule of reinforcement for pre-reactivation-treated animals and on a VR5
schedule for post-reactivation animals. The next day, lever-pressing behavior
was measured for 30 min during extinction and then 30 min during cue-
reinstatement conditions. It was hypothesized that Ch-ABC given either pre- or
post-reactivation would disrupt reconsolidation and attenuate cue-induced lever
pressing. Ch-ABC did not affect extinction rate in any conditions; however,
Ch-ABC reduced cue reinstatement in the pre-reactivation Ch-ABC cohort
when memory was reactivated by the VR5 (but not the FR1) session, indicating
that memory is reconsolidated only when a novel reactivation session is used.
Surprisingly, Ch-ABC given post-reactivation increased cue-reinstatement. Our
results suggest that PNNs in the mPFC may be a target for novel therapies in
cocaine addiction, but further exploration of the time-dependent differences in
outcome is necessary.

S4. Cocaine-Induced Reinstatement Alters Parvalbumin

Cells in the Rat Medial Prefrontal Cortex Following
Removal of Perineuronal Nets
Angela Gonzalez*, Emily Jorgensen, John Harkness, Sue Aicher, Deb Hegarty,
Travis Brown, Barb Sorg
Parvalbumin (PV)-positive cells are GABAergic fast-spiking interneurons that
modulate the activity of pyramidal neurons in the medial prefrontal cortex
(mPFC) and their output to brain areas associated with learning and memory.
The majority of PV cells are surrounded by a specialized extracellular matrix
structure called the perineuronal net (PNN). We have recently shown that
cocaine exposure and cocaine-associated memories can alter the staining
intensity of PNNs and PV intensity in the mPFC. Moreover, we have shown
that removal of PNNs with the enzyme chondroitinase ABC (Ch-ABC) in the
mPFC prevents the consolidation and reconsolidation of cocaine-associated
memories. Here we examined the time course of changes in PV intensity
following cocaine-induced reinstatement after removal of PNNs. Rats were
trained for cocaine-induced conditioned place preference (CPP) for 6 days.

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Rats then underwent extinction training for 8-12 days. After the last extinction
training, rats were microinjected with Ch-ABC in the prelimbic (PL) mPFC.
Re-exposure to the CPP context occurred 72 hours after the microinjection
of the enzyme with a cocaine priming injection (10 mg/kg ip). Rats were
sacrificed either 2 hr, 6 hr, or 48 hr following reinstatement. A separate cohort
of rats was sacrificed prior to any cocaine re-exposure as a baseline control (t = 0
hr). Brain slices were stained and quantified for PV and PNNs. We are currently
measuring the intensity of PV and PNNs and excitatory and inhibitory puncta
apposing PV cells surrounded by PNNs. Our preliminary data suggest that
PV intensity increases at 2 and 6 hr that normalizes by 48 hr. Our data also
indicate that there are changes in the intrinsic firing properties of PV cells 2 hr
after cocaine priming. These findings suggest that there are rapid changes in
PV content, which may in turn regulate output of the mPFC and reinstatement
behavior.

S5. Contributions of Prelimbic-Striatal Circuits to Sex-

Based Differences in Risk-Based Choice
Maria Jose Navarro, Michael Saddoris*
Brain regions involved in reward seeking and motivation, such as dorsomedial
striatum (DMS) and nucleus accumbens (NAc), are particularly vulnerable to
chronic effects of drugs of abuse. Regular use of psychostimulants like cocaine
cause striking differences in neural signaling in these regions, such as poor
encoding of reward-predictive cues by NAc neurons, and abnormal phasic
release patterns of dopamine to similar associative cues. These basic encoding
properties in Pavlovian conditioning are thought to contribute to more complex
deficits in neuroeconomic choice, such as impulsivity, inflexible cognition and
abnormal risk-taking behaviors. However, risk-based choice involves a number
of competing processes such as the evaluation of the anticipated reward, the
probability and severity of the risk, cost-benefit tradeoff assessments, and
updating strategies in the face of payoffs/loss. Little is known which of these
discrete processes are impacted by repeated cocaine self-administration in
decision-making circuits, or indeed whether these impacts vary between sex.
Here, we used the Balloon Analogue Risk Task (BART), a paradigms originally
created for human studies, to evaluate these discrete elements of risk-taking
behavior impacted by drug experience. BART task provides a distinct model
to assess different steps of the decision-making process, as animals must
balance a desire to press to earn for more rewards versus escalating risk that the
trial will “bust” and erase earned potential rewards. In this task, we recorded
simultaneously in prelimbic (PL) cortex and its known striatal targets, NAc and
DMS during this task in both male and female cocaine-experienced subjects
and drug-naïve controls. Surprisingly, we found significantly greater effects of

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sex than drug on this approach, males displaying more risk-taking behavior
than females. Subsequent neural analyses will be assessed to understand the
individual differences contributing to these behavioral profiles.

S6. KCNQ3 Overexpression Differentially Modulates Cue-

Induced Reinstatement of Heroin-Seeking in High- Versus
Low-Risk Rats
Britahny Baskin*, Kes Luchini, Susan Ferguson
Opioid addiction is a chronic, relapsing disorder, characterized by bouts of
compulsive drug intake, protracted withdrawal states, and a high vulnerability
to relapse. Opioid addiction in the United States is a national public health
emergency because it is responsible for the deaths of more than half a million
individuals since 2000 and there is a lack of pharmacotherapeutics for long-term
treatment. Similar to other addictive behaviors, opioid addiction is believed
to arise in part due to aberrations within the mesocorticoaccumbens loop, a
network involved in associative learning, decision-making, and motivation.
Central to this circuit is neurons in the ventral tegmental area (VTA) which
are hyperexcited by drug-associated cues following opioid use. The KCNQ2/3
channels expressed on dopaminergic VTA neurons, fine-tune their activity by
decreasing excitability and have been associated with drug-craving following
alcohol or nicotine use. Although they may regulate long-term neuroplasticity
in VTA dopamine neurons following opioid use, the functional role of KCNQ
channels in regulating relapse behaviors is unknown. Here we use a model
of heroin self-administration in male Sprague-Dawley rats to probe relapse
behaviors following extended drug abstinence. Using behavioral metrics from
intermittent access, progressive ratio, and extinction sessions, an addiction
severity score was calculated for each rat classifying animals into those with
that have low or high levels of addiction-like behaviors (low-risk or high-
risk). Animals then went through 30 days of forced-abstinence and a virus
overexpressing KCNQ3 (or sham) was infused into the VTA to maximally
express on the day of their cue-induced reinstatement session. Overexpression
differentially modulated heroin seeking causing low-risk animals to increase
heroin-seeking compared to sham low-risk animals, while high-risk animals
increased responding relative to their sham controls. Tissue was collected
following reinstatement sessions to validate viral placements and KCNQ3
expression. These findings will add to our understanding of how KCNQ
channels regulate neurons in the VTA following heroin use, and how they
regulate cue-induced heroin-seeking following long periods of drug abstinence.

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S7. Open Board

S8. Gut Microbial Compositions Associated With Cocaine

Self-Administration in Adult Male Rats
Gregory Suess, Giordano de Guglielmo, Olivier George, Benoit Chassaing, Kyle
Frantz*
Bacterial communities in the gut participate in a gut-brain axis that influences
the nervous system. Disruption in microbial composition is associated with
neuropsychiatric disorders, including drug abuse. It remains unknown,
however, whether gut microbial profiles can predict an addiction phenotype
before it emerges, or reflect drug experience after it occurs. This study tested
the hypothesis that the gut microbiota can predict and reflect susceptibility to
cocaine reinforcement, using behavioral data and biological samples from the
Cocaine Biobank. Adult male rats were catheterized and allowed to acquire
lever-pressing maintained by iv cocaine infusions in 2-hr daily sessions (10
days), followed by progressive ratio (PR) testing. Rats were transitioned to
long-access daily sessions (6-hr each, 14 days), also followed by a PR test and
alternating blocks of footshock testing, long-access, and PR. Fecal samples were
collected at three time points, prepared for Illumina sequencing of bacterial
16S rRNA genes, and analyzed for diversity (QIIME 1.9.0). As expected, rats
varied in levels of cocaine-related behavior, such that a quartile split identified
high and low responders on each measure and an overall addiction index.
Although beta diversity at baseline did not predict membership in high or
low addiction quartiles, the genus Allobaculum was over-represented in high
responders, whereas Akkermansia muciniphila was over-represented in low
responders. After long-access, bacterial communities did cluster by high vs.
low addiction index, and again the genus Allobaculum was over-represented
in high responders. Alpha diversity and functional impact of these differences
are under investigation and will expand these findings. Identification of specific
bacterial groups associated with high vs. low cocaine responsivity highlights
new approaches to prediction and treatment of addiction, as pre- and probiotic
therapies might promote a healthy gut and reduce addiction.

S9. Synthetic Cathinone Mephedrone Causes Chronic

Leakage of the Blood Brain Barrier by Downregulation of
Membrane-Bound Claudin-5
Tetyana Buzhdygan*, Scott Rawls, Servio Ramirez
Synthetic cathinones, such as mephedrone, are an emerging class of designer
drugs consumed for psychostimulant and hallucinogenic effects. Recently
in the US, the use of synthetic cathinones (bath salts) have dramatically
increased, especially among adolescent and young adult populations. Spike of

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overdose-related fatalities and adverse effects, including severe brain edema and
vascular damage, calls for detailed investigation of the effects of cathinones on
cerebral microvascular endothelial cells
We investigated the effects of mephedrone, a synthetic cathinone that is most
frequently found in the designer drug formulations linked to the most adverse
complications, on the expression of tight junction proteins and the integrity of
the endothelial cell monolayer.
We showed that exposure of fetal human brain microvascular endothelial cells
(f HBMVEC) to mephedrone resulted in the significant loss of membrane-
bound, but not cytosolic fraction of the claudin5 protein (-52.5%, at 24hs).
Additionally, functional analyses revealed that mephedrone caused dramatic
loss of BBB integrity as measured by transendothelial electrical resistance (-50%
from untreated, at 24hs). Chronic exposure to the mephedrone caused a 5-fold
increase in the permeability for small (3kDa) but not large sized molecular
weight tracers (40kDa and 70kDa FITC-dextran), suggesting enhanced
paracellular route.
To date, these are the first studies to report that mephedrone causes endothelial
damage and BBB leakiness thereby likely affecting the capacity of the BBB to
protect the brain from bloodborne solutes and pathogens. Moreover, our data
suggest that cathinones may contribute to drug use-associated CNS infections
and neuroinflammation.

S10. Pharmacotherapy Prescribing Patterns in Alcohol

Use Disorder (AUD) for Patients Enrolled in the Riahealth
Treatment Program (RHTP)
John Mendelson*, Julien Stainback, Robert Nix, David Deacon
Background: Despite many safe and effective AUD pharmacotherapies little is
known about anti-alcohol prescribing practices. For most diseases, combination
pharmacotherapies are superior to monotherapy yet there are few reports on
the use of rational drug combinations in AUD. Here we report the rate, duration
and clinical outcomes for anti-alcohol drugs prescribed to patients treated
for AUD by RiaHealth. Methods: The RHTP is an AUD telehealth treatment
program deployed on smartphones. Alcohol use is quantified with 1-2X/day
breath alcohol concentrations (BAC) and patients are treated with medications
and coaching. Prescription data were obtained through the Ria application
and EHR interfaces which tracks all prescribing to Ria patients. Prescribing
of Naltrexone (NTX), acamprosate (ACAM), gabapentin (GABA), baclofen
(BAC), and topiramate (TOP) were assessed. Results: From 1/2017-9/2019
816 Ria patients were prescribed anti-AUD meds. At treatment initiation NTX
was prescribed to 83.1% followed by GABA (7.6%), NTX-GABA (4.0%),
ACAM (2.57%) Baclofen (0.98%) and TOP (0.86%). At 6 months NTX
has decreased to 67.61% and NTX-GABA had increased to 12.68%, ACAM

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decreased to 2.35%, Baclofen increased to 2.35% and TOP increased to 1.41%.
At 6 months, 47% of patients remain in treatment and mean BAC declined
from 0.08 to 0.03 g/L (66%). Non-drinking days increased from 1.8 to 3.9
days/week. Conclusions: Medication management in AUD is effective, safe
and well tolerated and can be improved with telehealth. In the Ria cohort NTX
is the most commonly prescribed monotherapy and NTX-GABA is the most
commonly prescribed combination. NTX-GABA combinations appear safe and
well tolerated but more research is needed to assess therapeutic switching and
synergy. Conflict of Interest: All authors are employees of Ria Health

S11. Decoding Impulsive Decision-Making: Toward

Understanding No Friends on Powder Days
Lucas Dwiel, Aboubacar Cherif, Alan Green, Wilder Doucette*
Impulsive decision-making (IDM) is observed across psychiatric disorders,
from ADHD and bipolar to substance use disorders. Variation in IDM
can be measured in animals and humans using the delay discounting task
(DDT). In patients, high impulsivity relates prospectively to problematic
behaviors—gambling, substance use, violence, and suicide—and also predicts
non-response to treatment and risk of relapse of the underlying psychiatric
disorder. In order to develop personalized treatments that target IDM at a
neural systems-level, the known correlation between neural oscillations and
DDT performance needs to be more rigorously evaluated. We determined
if neural oscillations (local field potentials-LFP) recorded from the cortical-
striatal system (known to regulate IDM) could predict innate and stimulation-
induced variation in DDT performance. Male and female Sprague-Dawley rats
were trained in the DDT, implanted with stimulation and recording electrodes
(targeting the infralimbic cortex, orbitofrontal cortex, nucleus accumbens
shell and core), and LFPs were recorded in neutral contexts as well as during
the DDT (with and without deep brain stimulation). LFP features of power
and coherence were used as predictors in machine learning models to classify
delay discounting performance (average performance across sessions - trait;
session to session performance - state; or trial-to-trial choices). We found that
the information about trait and state impulsivity resided mostly in measures
of connectivity between brain regions, whereas the information about trial-
to-trial decision making was reflected in LFP power. Overall, low frequency
(delta and theta) LFP features contained the most information about IDM and
stimulation targeted to the infralimbic cortex modulated low frequency LFP
features resulting in altered DDT performance. Overall, this data goes beyond
correlation to link low frequency features of neural oscillations to impulsive
decision-making.

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S12. The Immediate Response to Trauma in Adulthood
Combined With Early Life Stress Predicts Development of
Post-Traumatic Stress Disorder
Felicia Gould*, Gabrielle Hodgins, Philip Harvey, Mackenzie Jones, Vasiliki
Michopoulos, Barbara Rothbaum, Kerry Ressler, Charles Nemeroff
Although many reports have documented the relationship between early life
stress (ELS) and development of later life psychopathology including Post-
Traumatic Stress Disorder (PTSD), few prospective studies of civilians with
a history of ELS immediately after trauma exposure have been conducted.
Identification of individuals at greatest risk for the development of PTSD
likely could lead to early interventions averting its development of PTSD. The
present study aimed to determine whether participants with a history of ELS
would differ in their vulnerability to PTSD following a Criteria A traumatic
event. Further, we aimed to examine the immediate severity of psychological
symptoms characteristic of PTSD and determine whether the severity of
these reactions predicted development of PTSD. Participants (N=712) were
recruited from the Emergency Departments at Jackson Memorial Hospital
in Miami and Grady Memorial Hospital in Atlanta immediately following a
traumatic experience. Follow-up assessments were conducted at 1-, 3-, and
6- months post-trauma. Early life trauma predicted immediate PTSD-related
reactions, which in turn predicted the persistence of PTSD symptoms. PTSD
severity at each assessment was the only predictor of PTSD severity at later
follow-up. Overall, the current findings suggest that the initial trauma reaction is
a strong predictor of PTSD development, which is predicted by early life trauma
experience severity.

S13. Behavioral Adaptations in a Relapsing Mouse Model of

Colitis
Chelsea Matisz*, Aaron Gruber
Inflammatory bowel disease (IBD) is characterized by relapsing periods of
gut inflammation, and is comorbid with depression, anxiety, and cognitive
deficits. Animal models of IBD that explore the behavioral consequences
almost exclusively use acute models of gut inflammation, which fails to
recapitulate the cyclic, chronic nature of IBD. This study sought to identify
behavioral differences in digging, memory, and stress-coping strategies in mice
exposed to one (acute) or three (chronic) cycles of gut inflammation, using the
dextran sodium sulfate (DSS) model of colitis. Similar levels of gut pathology
were observed between acute and chronically exposed mice, although mice
in the chronic treatment had significantly shorter colons, suggesting more
severe disease. Behavioral measures revealed an unexpected pattern in which
chronic treatment evoked fewer deficits than acute treatment. Specifically,

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acutely-treated mice showed alterations in measures of object burying, object
recognition, object location memory, and stress-coping (forced swim task).
Chronically-treated animals, however, showed similar alterations in object
burying, but not the other measures. These data suggest an adaptive or
tolerizing effect of repeated cycles of peripheral gut inflammation on mnemonic
function and stress-coping, whereas at least some other behaviors continue to
be affected by gut inflammation. We speculate that the normalization of some
functions may involve the reversion to the bassline state of the HPA axis and/or
microglia, which are both activated by the first exposure to the colitic agent.

S14. Unrestricted Chemogenetic Activation of

Norepinephrine Neurons Impairs Attention in the Mouse
Continuous Performance Test (rCPT)
Andreas Sørensen*, Leonie Posselt, Søren Jørgensen, Ulrik Gether
The prefrontal cortex (PFC) is known to be an important area regarding
impulsivity and attentional control, and believed to be substantially influenced
by norepinephrine (NE) and dopamine (DA) levels. The popular inverted
U-shaped theory of attention argues that optimal attentional performance
depends on balanced levels of NA and DA signaling in the PFC. While previous
studies have consistently demonstrated that lack of NA signaling impairs
attention, it remains unknown how such cognitive performance is influenced
by excessive NE levels. In this study, we took advantage of the excitatory
Dq-DREADD, representing a chemogenetic tool that allows powerful control
of neurons in vivo, to address how visual attention in the rCPT is influenced
during selective activation of NE neurons. To restrict the manipulation towards
locus coeruleus (LC)-PFC projecting neurons, we applied a dual viral approach
using retrogradely transported CAV2-Cre vector injected into PFC and Cre-
dependent AAV vector expressing Dq-DREADD injected into LC. While
Dq-DREADD expression was clearly observed in LC in this case, activation of
NE neurons did not induce any effects on attentional behavior. On the other
hand, if the Dq-DREADD manipulation was directed towards all NE neurons in
the LC, attentional performance was severely impaired. This effect was dose-
dependent (i.e. CNO) and did not influence any gross motor functions in the
rCPT, suggesting that optimal NE signaling is also required elsewhere than PFC
for appropriate attentional performance.

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S15. Examining the Mechanisms of Spatial Working
Memory Encoding and Retrieval in the Prefrontal-
Reuniens-Hippocampal Network
John Stout*, Amy Griffin
Spatial working memory (SWM) requires interactions between the medial
prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) that are supported
in part by connections via the nucleus reuniens (Re). While much work has
focused on how the mPFC and dHPC synchronize during SWM tasks, it
is unknown how these regions differentially interact with the Re during the
encoding and retrieval of spatial memories. To this end, we used multi-site
recording techniques while rats performed a T-maze delayed non-match to
position (DNMP) task and assessed how mPFC-Re-dHPC interactions differed
between the sample (‘encoding’ dominant) and choice (‘retrieval’ dominant)
phases. We focused our analyses in the epoch surrounding the entrance to
T-junction, the location that corresponds to a left/right decision-action, and
provide behavioral metrics that solidify the examination of this location. First,
we replicate that mPFC-dHPC theta coherence is higher on the choice phase
when compared to sample phase ( Jones and Wilson, 2005; Sigurdsson et
al., 2010; O’Neill et al., 2013) and demonstrate that dHPC-Re fast gamma
coherence is comparably higher on the sample phase. Then, we examined how
coherence changed between task phase as rats approached and entered the
T-junction. Prior to T-entry, we found that the mPFC-dHPC and mPFC-Re
groups exhibited higher theta coherence during choice phase with respect to
sample phase. For the dHPC-Re group, fast gamma coherence was again found
to be comparably higher during the sample phase, while slow gamma coherence
was higher during choice phase. Finally, we used granger prediction to show
a theta-specific mPFC-to-Re-to-dHPC lead relationship during memory
retrieval. Our coherence results provide novel insight into how the mPFC-Re-
dHPC network synchronizes to support the encoding and retrieval of spatial
memories while our granger findings support the hypothesis that mPFC-Re
projections may support the retrieval of SWM (Hallock et al., 2016).

S16. Sleep Disturbances in Mice During Chronic THC

Administration and Abstinence
Andrew Kesner*, Karina Abrahao, Matthew Pava, David Lovinger
The diagnosis of cannabis withdrawal is contentious because reliable, objective
measures of withdrawal from delta-9-tetrahydrocannabinol (THC), the major
psychoactive compound in cannabis, are generally difficult to observe. A known
consequence of chronic cannabis use in humans is altered sleep, and sleep
disturbances are often cited as a primary withdrawal symptom during cannabis
abstinence. Our lab has previously reported a role for endogenous cannabinoid

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signaling in sleep stability in mice, and in the current study we aimed to
determine if THC withdrawal-induced changes in sleep can be modeled in
rodents. Using electrocorticogram and electromyogram recordings from
chronically implanted mice combined with our fully automated sleep analysis
system to score sleep before, during, and after chronic injection of either THC
or vehicle control, we find that polysomnographic measures in mice treated
with THC indeed mimic clinical observations of altered sleep architecture
in human cannabis users. In particular, measurements obtained over six days
following cessation of THC treatment revealed that time spent in NREM
sleep was reduced largely because of a decrease in NREM bout duration.
Additionally, rapid eye movement (REM) sleep was reduced on the first day of
acute THC administration and was enhanced 6 days following treatment. The
augmentation in REM during the abstinence phase of the experiment could
be due to an increase in the number of REM bouts, and this effect persisted
throughout the 6 days of abstinence. None of these changes were observed
in controls. Paradoxically, the power of delta oscillations was no different
between THC and controls during the first day of abstinence, but THC mice
displayed markedly less delta power by the last day of abstinence. This suggests
that impairment of processes contributing to slow oscillations in the cortex
gradually begins to manifest over recovery from chronic THC exposure. To
our knowledge, this is the first murine model of a directly translatable non-
precipitated cannabis withdrawal symptom. These data open the door for
pre-clinical research efforts to study, and potentially treat, a primary withdrawal
symptom of cannabis use disorder.

S17. Mesoscale Collective Action in the Hippocampus: A

Thermodynamic Modeling Approach
Alex Sheremet*, Yu Qin, Andrew Maurer
Of the three scales of brain activity (micro-, meso- and macro-scale),
mesoscopic activity is the least studied. In the cortex, mesoscopic collective
action (MCA) manifests as propagating waves (e.g., Muller et al., 2018).
Dismissed often as marginally-significant neuron synchronization, MCA may
in fact be the main function of the cortex, as suggested by the non-hierarchical
(isotropic and homogeneous) structure of cortical layers, which favors MCA
over hierarchical microcircuit activity. This is consistent with the conjecture that
physical structures underlying cognition resemble biological systems, with no
design and no a priori function (Edelman and Gally, 2001). As such, collective
action might play an essential role in the integration of brain activity (e.g.,
Freeman 2010). Despite a few initial insights (Wilson and Cowan 1973, 1974;
and others) a consistent theory for MCA dynamics is still lacking. Because the
mesoscale is macroscopic with respect to microscopic processes, the wealth
of knowledge accumulated about microscopic physics cannot be directly

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extended to mesoscopic processes. We propose that the weak turbulence theory
(Zakharov, 1992) could provide the theoretical framework for studying self-
sustained MCA dynamics. Turbulence describes the internal energy balance in
nonlinear multi-scale systems with a large number of components. Nonlinear
interaction between scales results in cross-scale flows of energy and other
conserved quantities, known as the “turbulent cascade” (Richardson, 1922;
Kolmogorov, 1941). We show that the observed evolution of MCA energy
balance (LFP spectra and bispectra) in the hippocampus are consistent with
mesoscopic weak turbulence. We derive the governing equations in a general
conservation form, that generalize existing models (Wilson-Cowan, 1974,
Wright and Liley 1995; and others). We derive dynamical equations for the
evolution of the power spectral density, and investigate their averaged (kinetic)
behavior. The turbulent model predictions of the theta-gamma phase coupling
characteristics are consistent with observations. Turbulence holds the promise
to provide a consistent theoretical framework for modeling hippocampal energy
processes, including the persistent question about the significance of power law
spectra and their slopes.

S18. Effects of a Natural Anti-Inflammatory Agent in a

Model of Alzheimer’s Disease
Jason Eriksen*, Tasha Womack
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder
that is the most common cause of dementia in aged populations. A
substantial amount of data demonstrates that chronic neuroinflammation
can accelerate neurodegenerative pathologies, while epidemiological and
experimental evidence suggests that use of anti-inflammatory agents may be
neuroprotective. In AD, chronic neuroinflammation results in the upregulation
of cyclooxygenase and increased production of prostaglandin H2, a precursor
for many vasoactive prostanoids. While is well-established that many
prostaglandins can modulate the progression of neurodegenerative disorders,
little is known about the role of prostacyclin (PGI2) in the brain. We have
conducted studies to assess the effect of elevated prostacyclin biosynthesis
in a mouse model of AD. Upregulated prostacyclin expression significantly
worsened cognitive abnormalities, accelerated amyloid pathology, and damaged
the neurovasculature. PGI2 overexpression selectively increased soluble
amyloid-β 42 production, total amyloid accumulation, and burden. PGI2
altered microvessel length and branching, and PGI2 expression in combination
with amyloid was more detrimental than amyloid expression alone. In vitro
studies demonstrated that increased prostacyclin signaling inhibited microvessel
formation and selectively altered gamma secretase subunit expression. Our
findings demonstrate that chronic prostacyclin expression plays a novel and
unexpected role that hastens the development of the AD phenotype.

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S19. Open Board

S20. IRF8 ASOs Modulate Microglia Responses to an

Inflammatory Insult
Fredrik Kamme*, Christine Hong, Curt Mazur, Holly Kordasiewicz
Microglia have become of central interest in a range of neurodegenerative,
traumatic and affective disorders. A rapidly growing body of literature has
demonstrated a range of microglial activation states and functions in both
humans and experimental animals.
Antisense oligonucleotides (ASOs) reduce target protein expression by
hybridizing to the target RNA and recruiting RNAseH1, resulting in the
cleavage and degradation of the target RNA and reduction of expression of the
protein. As pharmacological agents, ASOs exhibit high target specificity and
an ability to target most RNAs. Together with a rapid development path for
ASO therapeutics, ASO technology is a unique platform to explore biology in
experimental animals as well as translating new discoveries into human drugs.
We have developed ASOs for mouse IRF8 to explore the role of this central
transcription factor in microglia responses to injury and disease. IRF8 ASOs
were tested in a model of systemic inflammation, triggered by an intraperitoneal
LPS administration. After immune challenge, microglia were isolated and
analyzed by RNA sequencing. As part of the evaluation, we characterized non-
target sequence dependent effects of ASOs on microglia in vivo.
The results show that ASO effects on microglia in vivo are target-sequence
specific, demonstrating that ASOs are a suitable platform to modulate microglia
in vivo. Knockdown of IRF8 was efficient, long lasting and had significant
effects on microglia inflammatory responses to a systemic LPS challenge.

S21. Fox DEN: Novel Data Sharing Platform for Sharing

Patient Reported Health Information and Genetic Data
From the Largest Parkinson’s Cohort Worldwide
Luba Smolensky*, Ninad Amondika, Lindsey Riley, Karen Crawford, Scott Neu,
Caroline Tanner, Ethan Brown, Monica Korell, Vanessa Arnedo
Fox Data Exploration Network (DEN): Novel data sharing platform for
sharing patient reported health information and genetic data from the largest
Parkinson’s disease cohort worldwide.
Parkinson’s disease (PD), which is the second most common neurodegenerative
disease, has a wide range of phenotypes and the rate of progression varies
significantly among the affected. Research data from observational studies,
particularly those with remote data collection, offer a mechanism to study the
heterogeneity and variability in disease.

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To this end, patient-reported outcome data and genetic data from Fox Insight
(FI), an online study of more than forty thousand people with and without
PD, are centralized in the Fox Data Exploration Network (DEN) platform
([Link] and available to researchers. Within
the platform, researchers may explore and visualize more than 2,400 self-
reported health attributes. In addition, Fox DEN allows researchers to define
different sub-cohorts using multiple variables, as well as perform different types
of statistical analyses. Researchers are encouraged to use the analysis tool for
cohort building and exploratory statistical modeling. Fox DEN also serves as
the data download mechanism for researchers who prefer to conduct analyses
on the cohort data using external statistical tools.
In more detail, Fox Insight (FI) is an online study which integrates regularly
administered validated patient-reported outcomes (PRO) instruments and
novel PD-related questionnaires. The surveys follow a regular cadence and
pattern dependent on the participant’s self-reported diagnosis. Genetic data
collection in people with PD (PwP), and one-time surveys focused on specific
topics also complement the study.
The Fox Insight cohort consists of 72% PwP with a mean age of 65.8, and mean
disease duration of 6.61 years. More than 5450 participants have linked their
genetic information through 23andMe.

S22. GABA and Glycine Neurons From the REM Sleep

Controlling Ventral Medullary Region Inhibit Hypoglossal
Motoneurons: A Mechanism for Obstructive Sleep Apnea
David Mendelowitz*, Olga Dergacheva
Obstructive sleep apnea (OSA) is a common disorder characterized
by repetitive sleep related losses of upper airway patency that occur
most frequently during rapid eye movement (REM) sleep. Hypoglossal
motorneurons (HMNs) play a key role in regulating upper airway muscle
tone and patency during sleep. REM sleep active GABA and glycine neurons
in the ventral medulla (VM) induce cortical desynchronization and skeletal
muscle atonia during REM sleep; however, the role of this brain region in
modulating hypoglossal motor activity is unknown. We combined optogenetic
and chemogenetic approaches with in-vitro and in-vivo electrophysiology,
respectfully, in GAD2-Cre mice of both sexes to tests the hypothesis that VM
GABA/glycine neurons control the activity of HMNs and tongue muscles. Here
we show there is a pathway originating from GABA/glycine neurons in the
VM that monosynaptically inhibits brainstem HMNs innervating both tongue
protruder genioglossus (GMNs) and retractor (RMNs) muscles. Optogenetic
activation of ChR2-expressing fibers induced a greater postsynaptic inhibition
in RMNs than in GMNs. In-vivo chemogenetic activation of VM GABA/
glycine neurons produced an inhibitory effect on tongue electromyographic

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(EMG) activity, decreasing both the amplitude and duration of inspiratory-
related EMG bursts without any change in respiratory rate. These results
indicate that activation of GABA/glycine neurons from the REM VM inhibits
tongue muscles via a direct pathway to both GMNs and RMNs and this
inhibition likely plays an essential role in REM sleep associated upper airway
obstructions that occur in patients with OSA.

S23. Histological Evidence for Diffusion Rather Than

Convective (“Glymphatic”) Bulk Flow of Solutes in the
Cerebrospinal Fluid (CSF)
Miles Herkenham*
Cerebrospinal fluid (CSF) is formed in the choroid plexus and flows through
the ventricles, subarachnoid spaces, and interstitial spaces, eventually being
cleared into the bloodstream. Solutes in the CSF travel throughout this
continuous compartment, which is important for two reasons. First, solute
clearance from the brain is important for removal of toxic molecules. Second,
neuroactive substances, released at specific sites are also suggested to reach
respective distant target cell receptors by diffusion through the extracellular
spaces (termed “parasynaptic communication” or “volume transmission”).
In 2000, we published a histological demonstration of CSF flow of large-
molecular-weight solutes from the ventricles into brain’s interstitial spaces
(Proescholdt, Neuroscience; 95: 577-92). The tracer [C-14]inulin was
delivered via cannulas into the lateral ventricle of rats. Five minutes after
infusion, tracer could be seen by autoradiography to rapidly travel throughout
the ventricles and subarachnoid spaces, and from these locations, it diffused
into the interstitial spaces. By 30 min, tracer had moved into the parenchyma,
and by 4 h, the brain was filled with tracer. Perivascular travel was observed, but
it was not a major contributor to the distribution.
In 2012, Nedergaard’s group published on CSF flow using fluorescent dextran
injected into the ventricles and failed to see diffusion but rather saw mainly
perivascular flow (Iliff, Sci Transl Med; 4: 147ra111). Based on this and the
involvement of aquaporins on astrocyte end feet, they proposed “glymphatic
flow” of convective CSF flow.
Since then, there has been controversy over whether CSF flow through the
extracellular spaces is convective or diffusive. The pattern of inulin flow clearly
supports the diffusive flow interpretation. Apparently inulin, a 5 kDa inert
carbohydrate, is a better marker of interstitial transport than large dextrans,
which can be pinocytosed during transport.

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S24. Late Perampanel Treatment Stops Midazolam-
Refractory Seizures in an Experimental Model of Status
Epilepticus
Jerome Niquet, Ireri Franco Estrada, Claude Wasterlain*
Objective: To assess the effectiveness of perampanel, a specific antagonist for
AMPA-type glutamate receptors, as a second-line treatment of benzodiazepine-
unresponsive Status Epilepticus (SE).
Background: SE responds poorly to benzodiazepines, especially when
treatment is delayed. Experimental data show that SE causes an early
maladaptive internalization of synaptic GABAA receptors, which may explain
benzodiazepine pharmacoresistance, along with a migration of NMDA and
AMPA receptors (AMPAR) towards synapses, increasing glutamatergic
excitation. Topiramate, an AMPAR antagonist, is often effective in refractory
SE, and the stronger AMPAR antagonist perampanel deserves evaluation in the
treatment of SE.
Design/Methods: SE was induced in adult male Sprague-Dawley rats by high-
dose lithium/pilocarpine, and EEG/video was recorded for 18 hrs. Midazolam
(1 mg/kg; ip) was injected 40 min after SE onset. Perampanel (0.5, 1 or 2 mg/
kg, ip) or valproate (270 mg/kg) was injected 20 min following midazolam if SE
continued.
Results: During the first hour following treatment with perampanel 2 mg/kg
(−84 ± 314; p<0.0001) or 1 mg/kg (170 ± 410; p<0.01), but not valproate 270
mg/kg (453 ± 393, NS), EEG power was decreased compared to midazolam
alone (671 ± 208). Perampanel 2 mg/kg (median -514; interquartile range:
-1072 to -73; p<0.001) or 1 mg/kg (207; -675 to 758; p<0.05), but not
valproate 270 mg/kg (1027; 396 – 3346, NS), also significantly reduced the
EEG power integral over the 6 h posttreatment when compared to midazolam
alone (2407; 1557 to 3813). In addition, perampanel 2 mg/kg reduced the time
needed for EEG amplitude to decline to twice the pre-seizure baseline (median
= 11 min; interquartile range: 6 min – 31 min), compared to midazolam (42
min; 33-77 min; p < 0.05), suggesting earlier SE termination.
Conclusions: Perampanel is potent in stopping midazolam-refractory SE even
when given 60 min following SE onset in this animal model of severe SE.

S25. Distinct Properties of GABA-A Receptors at Synaptic

and Extraysnaptic Sites Shape Circuit Patterns During
Seizure Evolution
David Naylor*
GABA-ARs with gamma2 subunits mediate phasic inhibitory postsynaptic
currents (IPSCs) in hippocampal granule cells to brief high concentration
transmitter release and rapidly desensitize to low-level tonic or brief

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hi-frequency pulsatile GABA exposure. Conversely, extrasynaptic GABA-ARs
with delta subunits are non-desensitizing, have greater GABA affinity, and are
responsible for tonic inhibitory currents in response to low concentrations
of extracellular GABA, but also detect synaptic ‘spillover’. With convulsant
stimulation and seizure initiation, loss of synaptic inhibition occurs with
increases in extracellular GABA (~1uM). Computational models of GABA-
ARs optimized to fits of synaptic IPSCs, extrasynaptic tonic currents, and
multisynaptic evoked IPSCs simulated GABAergic responses for different
circuit conditions. Synaptic receptors desensitize with 90% loss of inhibition
at 160 Hz after 100 msec, simulating epileptic ‘fast ripples’. Recovery from
desensitized states occurs by 10 sec, but superimposed low frequency activity
(~0.5 Hz) and/or low level GABA (< 1uM) sustains the loss of synaptic
inhibition keeping a significant proportion of postsynaptic GABA-ARs
desensitized. Composite models of synaptic and extrasynaptic GABA-ARs
show hi-frequency stimulation promotes GABA spillover, and only a few
extrasynaptic delta subunit-containing receptors (~ 4 per synapse vs. 36
postsynaptic GABA-ARs) account for 60% of the current of evoked IPSCs,
prolonging and broadening the spatial extent of synaptically-released GABA
and favoring network slowing. At 3-6 Hz, 10-20 % of synaptic GABA-ARs
remain desensitized sustaining inhibitory loss while spillover to extrasynaptic
GABA-ARs supports hypersynchronous oscillations. In summary, evidence
supports a mechanism of seizure evolution with initiation by fast-rhythmic
activity and loss of synaptic inhibition progressing to slowed synchrony,
mediated by a dynamic shift of activation from synaptic to extrasynaptic
GABA-ARs.

S26. Development of a Novel Locomotor Behavioral

Assay to Evaluate the Efficacy of Neurosphere-Mediated
Regeneration following CNS Injury
Taylor Schanel*, Melanie Rojas Hammani, Scarlyn De Los Santos, Raeden Gray,
Elizabeth Batsel, Sean Mondesire, Martin Oudega, Jeffery Plunkett
Development of suitable locomotor assays to assess functional recovery
following central nervous system (CNS) trauma can be an invaluable tool to
an investigator. Adult zebrafish (Danio rerio) has proven in recent years to be
a model system that can be useful to evaluate not only mutational defects of
the CNS but to also study perturbations involving direct injury or trauma. Our
laboratory has developed a locomotor assay to study fish locomotor swimming
movement in a current of water. Fish naturally swim in currents to maintain
physiological levels of oxygen in the blood and our assay exploits this natural
tendency. Once a baseline of current swimming was established, we performed
a 2mm deep traumatic brain injury (TBI) in the brainstem of an adult fish.
Our data show that there is a significant deficit in current swimming through

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approximately 7 days at which time recovery towards baseline behavioral
swimming levels commences. Next, we challenged the trends of recovery
seen in the baseline injury through transplantation of characterized stem
neurospheres. We developed the approximately 100 micrometer neurospheres
in rotating in vitro aggregate cultures. Once characterized using the neural
progenitor marker, neuroD1, specific quantities of aggregates were transplanted
into the TBI site. Initial data indicate that transplantation of neurospheres may
alter the pathway and time course of locomotor swimming recovery that is seen
in non-transplanted animals.

S27. Induction of Endogenous Reprogramming and

Dedifferentiation of Adult Neurons in a Model of Spinal
Cord Injury
Jeffery Plunkett*, Angelo Milli, Sebastian Mariategui, Martin Oudega
In contrast to the brain of mammals, fish and amphibians maintain multiple
proliferative neurogenic and stem cell niches well into adult life. These niches
provide a reservoir of cells that can be enabled for both central nervous system
(CNS) growth and repair following injury. The pathway of neurogenesis
in many model systems is often depicted as unidirectional by which stem
progenitors differentiate into adult neurons. In a challenge to the unidirectional
model are amphibians. In amphibians, CNS trauma causes reprogramming of
fully differentiated cells (i.e., dedifferentiation) preceding their proliferation
and (re-)differentiation and organization into new tissue. Our data demonstrate
that adult zebrafish (Danio rerio) are also capable of reprogramming and
dedifferentiating fully differentiated adult neuronal cells in response to
injury. Following complete spinal cord injury (SCI) in adult zebrafish, we
examined stem cell-related gene expression profiles in identified populations
of differentiated brainstem neurons with an axon projecting into the spinal
cord. Our data demonstrate that the neural stem cell progenitor cell markers
sox 2, neuroD1 and oct 4 (Pou5f1) are differentially expressed in identified
descending reticulospinal tract neurons during both acute and chronic phases
post-SCI. Analysis of the cell proliferation marker PCNA indicated that
these same neurons gained and lost the ability to divide during the acute and
chronic phases respectively and eventually re-expressed the maturing neuronal
marker HuC. These expression profiles suggest that the identified descending
reticulospinal tract neurons reprogram, dedifferentiate and re-differentiate
following SCI. We are currently examining axonal growth associated genes to
correlate our findings to regenerative events seen typically in the spinal cord in
adult teleost fish.

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S28. Chronic Glucocorticoid Exposure Primes the
Neuroinflammatory Response to Nerve Agent Sarin
Kimberly Kelly*, Lindsay Michalovicz, James O’Callaghan
Chronic exposure to the glucocorticoid corticosterone (CORT), at levels
associated with high physiological stress, can exacerbate CNS proinflammatory
responses to neurotoxic insults in animal models. Persistent sickness
behavior, a prominent component of Gulf War (GW) Illness, is associated
with neuroinflammation. Veterans of the 1991 GW were exposed to the
stresses of war, being prophylactically treatmented with the reversible
acetylcholinesterase (AChE) inhibitor pyridostigmine (PB), organophosphate
pesticides chlorpyrifos (CPO) and dichlorvos (DDVP) and potentially
the nerve agent sarin. We have previously shown CORT exacerbation of
the neuroinflammatory response to CPO, DDVP, and the sarin surrogate
diisopropyl fluorophosphate (DFP). Here, we confirm that sarin exposure also
causes a neuroinflammatory response that is exacerbated by chronic CORT
pretreatment. CORT (200 ug/mL in 0.6% EtOH) was given in the drinking
water for 1 week prior to Sarin administration at an LD20 dose (0.1 mg/kg,
s.c.) on day 8. Animals were euthanized at 6 hours and brains were dissected
and then frozen for RNA and protein analysis. RNAseq analysis of cortex
revealed 1535 genes that were significantly up-regulated in the CORT+Sarin
group. Of these 211 were significantly greater than Sarin alone. These 211
genes were interrogated with DAVID to find GO terms which included
cytokine production, MAP kinase phosphatase activity, and cytokine binding.
Kegg pathways include: cytokine-cytokine receptor interaction, Jak-STAT
signaling pathway, MAPK signaling pathway, and hematopoietic cell lineage.
The neuroinflammatory response was further confirmed with elevated pSTAT3
protein by ELISA and elevated neuroinflammatory cytokines and chemokines
mRNA(TNFα, IL6, CCL2, IL1β, LIF, and OSM) by qPCR. Together these
findings confirm those we have previously shown with sarin surrogate, DFP and
provide additional support for the hypothesis that GWI is a chronic, stressor-
primed, neuroinflammatory condition potentially instigated by the combined
exposures to stressors and irreversible AChE inhibitors.

S29. Damage to Thalamic Nucleus Reuniens Following

Postnatal Alcohol Exposure Suggests Alterations to
Prefrontal-Thalamo-Hippocampal Circuitry
Anna Klintsova*, Zachary Gursky
Individuals diagnosed with FASDs often display impairment in “executive
function” (EF) behaviors. Many behaviors included under EF umbrella require
coordination of the prefrontal cortex (PFC) and hippocampus (HPC). Recent
non-human primate and rodent studies have demonstrated that the midline

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thalamic nucleus reuniens (Re) is essential in coordinating PFC-HPC activity,
as selective Re inactivation impairs PFC-HPC synchrony and behavioral
performance on HPC- and PFC-dependent tasks.
In animal models, AE during the brain growth spurt targets structures,
undergoing differentiation, layer formation and synaptogenesis, including HPC
and PFC. Given Re critical role in coordinating PFC-HPC activity, we initially
quantified immunofluorescently-labeled neurons (NeuN+) and cell nuclei
(Hoechst33342-stained) in adult female Long-Evans rats exposed to 5.25 g/kg/
day AE on postnatal days (PD) 4-9. We observed a significant loss of neurons
in Re, but no change in non-neuronal cell number. All of these measures were
unaffected in the neighboring rhomboid nucleus, suggesting specificity of this
damage to Re within midline thalamus.
We next explored if there is a dose-dependent loss of neurons in the Re. Either
“high-dose” 5.25 g/kg/day (BAC ≈340 mg/dL) or “moderate-dose” 3.00 g/
kg/day (BAC ≈145 mg/dL) alcohol was delivered to male and female rats via
intragastric intubation. The data suggest that both doses of alcohol produced
significant NeuN+ cell loss in adulthood while neither dose resulted in altered
number of microglia (immunofluorescent labeling of Iba1 protein). High-
dose AE resulted in reduced Re volume, but moderate-dose AE did not alter
Re volume. These data indicate that moderate-dose AE is sufficient to induce
lasting damage in Re.
Taken together, our data suggest that Re is vulnerable to AE in development,
resulting in significant neuron loss at both high and moderate doses. AE at this
time in development does not appear to alter the number of glial cells (i.e., non-
neuronal cells or microglia) throughout life.
Supported by NIAAA 1 R21 AA026613-01 and R01 AA027269-01 to AYK;
NIH/NIGMS COBRE: The Delaware Center for Neuroscience Research Grant
1P20GM103653-01A1 to AYK.

S30. Multiple Circadian Oscillators Mediate Food

Anticipation in Rats
Christian Petersen, Ralph Mistlberger*
Early in the 20th century, long before the word ‘circadian’ (~24h) was coined,
Curt Richter (1922) reported that rats can anticipate a daily mealtime in an
otherwise time free environment. Later studies showed that food anticipation
exhibits formal properties of a clock-controlled rhythm entrained by periodic
food access, including circadian ‘limits to entrainment’, i.e., anticipation is
constrained to circadian feeding intervals (e.g., 24h but not 18h intervals).
Despite this constraint, rats and mice can anticipate at least two daily meals.
Conceptually, multiple meal anticipation could be mediated by a single clock
used to discriminate and remember the circadian phase of each mealtime, or
by multiple circadian clocks, each entrained to a unique mealtime. Despite

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the parsimony of the single clock model, we provide evidence for multiple
entrained oscillators. We find that rats can stably anticipate up to 4 daily meals,
without light-dark cues or the master circadian clock in the suprachiasmatic
nucleus. Remarkably, rats could anticipate 2 daily meals with different
periodicities (one meal at 24h intervals, a second at 25 or 26h intervals).
Importantly, during total food deprivation tests, both anticipation rhythms
persisted, with a periodicity that matched the feeding interval to which they
were synchronized. Math modeling supports the computational feasibility of a
multiple entrained circadian oscillator model.

S31. Effects of Loss of SAP-97 and SAP-102 on Synaptic

Plasticity During Motor Learning
Yixuan Pei*, Richard Roth, Elena Ortega, Han Tan, Andrew Wu, Richard Huganir
Learning and memory relies on synaptic plasticity mechanisms such as
long-term potentiation and depression mediated through the up- or down-
regulation of synaptic AMPA receptors (AMPAR). It has been shown that a
group of scaffolding proteins within the membrane-associated guanylate kinase
(MAGUK) family play a critical role in the regulation of AMPAR trafficking
in the post-synapse. Here, we investigate how the local deletion of MAGUK
scaffolding proteins, SAP-97 and SAP-102, in adult mice alter synaptic
AMPAR levels in the motor cortex and how loss of these proteins affects motor
learning. Therefore, we use viral expression of Cre recombinase in SAP-97 or
SAP-102 conditional knock-out mice followed by behavioral analysis through
motor training and molecular quantification through subcellular fractionation
and immunoblotting to study effects on synaptic protein levels. Given the
importance of synaptic AMPAR expression for proper learning and memory,
our results show how scaffolding proteins regulate synaptic composition of
AMPARs and their effect on motor learning in mice.

S32. AMPA Receptors Intracellular Trafficking: From ER

to Plasma Membrane
Françoise Coussen-Choquet*
AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission
in the central nervous system. Their abundance at the synapse is essential
for the establishment and maintenance of synaptic function. Many studies
characterized trafficking of AMPARs in spines at basal state or after induced
plasticity. Their synaptic localization is dependent on a highly dynamic
exocytosis, endocytosis and plasma membrane trafficking events. Our
hypothesis is that synaptic localization of AMPARs is also regulated by their

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earlier intracellular trafficking (ie: Endoplamic Reticulum (ER)-to-Golgi and
Golgi-to-plasma membrane). However, AMPARs post-ER trafficking toward
the plasma membrane still remains poorly understood.
Using a new biochemical tool combined with photonic live imaging, we
controlled and followed the dynamic secretion of tagged AMPAR subunits in
cultured rat hippocampal neurons. These approaches allowed us to characterize
the AMPARs trafficking firstly from the ER to the Golgi apparatus and secondly
from the Golgi to the plasma membrane.
We show that AMPARs require around 15-30 minutes to reach the Golgi
apparatus passing through ER exit sites. After 45-60 minutes, both GluA1
and GluA2 reach the plasma membrane. They are localized at synapses after
2-4 hours. Furthermore, we were able to visualize the vesicular trafficking of
homomeric GluA1 receptors. Since the scaffold protein SAP97 has been shown
to be involved in the intracellular AMPARs traffic via its PDZ interaction with
GluA1, we have studied its role in the GluA1 vesicular trafficking. We show that
an abolishment of the PDZ interaction between GluA1 and SAP97 alters the
GluA1 vesicular trafficking. We are studying how long term induced synaptic
activity is able to regulate intracellular of GluA1 containing AMPAR.

MONDAY, JANUARY 27, 2020 • 3:30 P.M. - 4:30 P.M. • JEFFERSON/MADISON

M1. Female Rats Express a More Addictive Phenotype

Than Male Rats During Intermittent-Access Heroin
Self-Administration
Timothy O’Neal*, Zackari Murphy, Garret Stuber, Susan Ferguson
Opioid addiction is a chronic, relapsing disorder, characterized by bouts of
drug-taking and drug-seeking. The current opioid epidemic is the leading cause
of accidental death among adults and was responsible for more than 70,000
deaths in 2017. Although opioid overdose deaths have historically been more
frequent in men, the death rate is rising faster in women due to a recent spike in
heroin abuse. Addiction develops in part from disruptions within the cortico-
basal ganglia circuit (C-BG), a network integral for learning, decision-making,
and motivation. However, whether these changes contribute to sex differences
in heroin addiction remains unknown. Here, we used a model of intermittent-
access heroin self-administration in female and male Sprague-Dawley rats.
Using behavioral metrics from self-administration, progressive ratio, extinction,
and cue-induced reinstatement sessions, an overall addiction severity score
was calculated for each rat. Female rats were found to express significantly
greater heroin-seeking behaviors (responding during drug-unavailable periods,
perseverative responding during extinction, responding during reinstatement)
than male rats. Interestingly, however, female rats did not differ from male
rats in heroin-taking behaviors (infusions per day, infusion rate across drug-
available periods, motivation to self-administer heroin). Tissue was collected

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following progressive ratio testing and extinction testing and processed for
single cell-sequencing using 3-level scRNA-seq, or following reinstatement
testing and processed for cFos immunohistochemistry. To complement these
self-administration experiments, we are currently using conditioned place
preference coupled with fiber photometry to investigate the role of the C-BG
in heroin reward. Together, these experiments will add to our understanding
of how key nuclei of the C-BG contribute to the development, expression, and
maintenance of aberrant behaviors associated with heroin addiction.

M2. Exercise Prevents Incubation of Cocaine and Nicotine

Craving and Multi-Triggered Relapse to Heroin
Marilyn Carroll*, Lydia Fess, Ben Dougen, Jack Smethells, Natalie Zlebnik
Background: Nicotine, cocaine, and heroin addiction have high rates of
morbidity and mortality in the US. Most treatments have low success rate as
with self-quit attempts. Hypothesis: treatment failures are due to incubated
craving that builds over weeks to months after cessation and treatment ends,
leading to relapse. Goal: to block incubation of craving and multi-triggered
relapse (MTR) elicited by a wide range of stimuli.
A. Incubation of Craving
Methods: 1. Establish iv cocaine (0.4 mg/kg) self-administration, in female and
male rats in operant chambers for 10 days of stable behavior.
2. Move rats to a different environment with access to a running wheel,
(stationary wheel for controls) for 3 or 30 days.
3. Rats were returned to their operant chamber to test relapse responding with
cues formerly available with cocaine. No drug was available.
Results: 1. Females ran at higher rates than males during the 3- and 30-day
incubation periods.
2. Relapse responding (on drug lever) after wheel access was higher in the
30-day (vs. 3-day) groups indicating incubated craving.
3. Wheel-running blocked incubation of cocaine seeking at 30 days in both
sexes. In males wheel-running also reduced craving after 3 days.
Conclusion: Exercise reduced incubation of cocaine seeking in females and
males.
B. Multi-triggered Relapse
1. Establish i.v. heroin (0.015 mg/kg) self-administration in female and
male rats for 10 stable days, then 21 days of extinction with a running- or
stationary-wheel.
2. Test relapse responding with priming conditions (heroin, caffeine,
yohimbine-stress, other drugs).
Results: 1. Females had more wheel revolutions than males.
2. Wheel running reduced lever responding in extinction (first 7 of 21 days).

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3. Wheel-running reduced relapse cued by heroin, caffeine, stress, and females
> males.
Conclusion: Exercise reduced MTR to heroin seeking in female and male rats.

M3. L-DOPA Decrease Oral Fentanyl Consumption

Ryan Farero*, Janet Lee, Hope Willis, Paul Phillips
Altered dopamine (DA) signaling is implicated in most contemporary theories
of drug abuse. Both drugs of abuse and the cues that are repeatedly paired
with drugs are capable of driving dopamine release in the nucleus accumbens
core (NAcc). Work from our lab has shown attenuated dopamine release
correlates with increased cocaine intake and demonstrated a causal relationship
between dopamine transmission and cocaine consumption. More specifically,
increased dopamine signaling during response-contingent drug cues in the
NAcc decreases cocaine consumption. Given that the attenuated transient
dopamine signals in the NAcc were specific to the drug-paired cue and not the
substance itself, we hypothesize that dopaminergic transmission mediates drug
satiation across multiple drugs of abuse. To test this hypothesis, the present
work investigates pharmacological interventions during two self-administration
behavioral assays in male and female rats. First, a two-bottle choice procedure
was utilized in which animals were provided access to fentanyl or water.
Administration of L-DOPA, the dopamine precursor, decreased fentanyl
consumption (p<0.05), but had no effect on water consumed (p>0.05).Within
the second task, an instrumental self-administration assay, animals responded
at a nose-poke port eliciting delivery of fentanyl and an audiovisual stimulus.
Administration of L-DOPA decreased the amount of active responding
(p<0.01) and fentanyl consumed (p<0.05). To further investigate the brain
loci mediating the observed effects L-DOPA was infused directly into the
NAcc. The results of injections into the NAcc were surprising, as L-DOPA had
a statistical trend to increase active responding (p=0.0994), but no change
in fentanyl consumed was observed (p>0.2). Overall these results support
the hypothesis that dopaminergic transmission mediates drug consumption.
However, further studies will need to be performed to identify the brain loci
responsible for the observed effects.

M4. Proestrus-Induced Decreases in Heroin Intake in

Female Rats
Mark Smith*, Sarah Ethridge, Abigail Gibson, Tallia Pearson, Huailin Zhang,
Madison Marcus, Kenzie Potter, Andrea Robinson
We previously reported that opioid intake decreases markedly during
proestrus in normally cycling female rats. The purpose of this study was to
determine if this effect could be artificially mimicked in ovariectomized rats

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(Experiment 1) and to determine the endogenous hormones mediating this
effect in intact rats (Experiment 2). Ovariectomized (Experiment 1) and
intact (Experiment 2) female rats were surgically implanted with intravenous
catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule
of reinforcement. In Experiment 1, ovariectomized rats were treated with
estradiol (or vehicle) 22 hours before and progesterone (or vehicle) 1 hour
before a test session to artificially mimic proestrus. In Experiment 2, the
effects of estrogen and progesterone receptor antagonists on heroin intake
were examined during proestrus in normally cycling rats. In Experiment 1,
estradiol administered 22 hours before a test session significantly decreased
heroin intake in ovariectomized rats; progesterone administered 1 hour before
a test session did not alter heroin intake and did not enhance the effects of
estradiol. In Experiment 2, the estrogen receptor antagonist raloxifene, but
not the progesterone receptor antagonist mifepristone, significantly blocked
proestrus-induced decreases in heroin intake. Collectively, these data indicate
that proestrus-induced decreases in heroin intake are mediated by estradiol
and not progesterone. These findings also suggest that the effects of ovarian
hormones on heroin intake differ from that previously reported for other drugs
(e.g., stimulants).

M5. Prior Cocaine Self-Administration Differentially

Alters State Encoding in Distinct Dorsomedial Striatal
Neuron Populations in Rats
Lauren Mueller*, Melissa Sharpe, Thomas Stalnaker, Andrew Wikenheiser, Geoffrey
Schoenbaum
When the rules that govern our actions change, it is useful to learn about
the new situation in a way that preserves old learning, building a library of
associations that can be deployed as needed to match the current context. One
way to achieve this is to compartmentalize learning about different contexts
into distinct “states”, each containing information relevant to a particular
scenario. Using inputs from the orbitofrontal cortex, cell populations within
the dorsomedial striatum (DMS) work together to maintain such state-specific
associations. Since drugs of abuse are known to disrupt state-dependent
behaviors and decision making, neural encoding of state within the DMS may
be impaired by drug exposure.
Here, we assessed how a history of cocaine self-administration affected neural
representations of state in medium spiny neurons (MSNs) and fast-spiking
interneurons (FSIs), two of the major cell populations of the DMS. First, rats
self-administered either sucrose or cocaine for two weeks. Several weeks later,
single-unit activity was recorded while rats performed an odor-guided decision-
making task comprised of two blocks of trials, or “states”. In one state, odor cues
were delivered to a central port and signaled the availability of a large reward

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from one fluid well and a small reward from another well. In the second state,
the odor-reward size contingencies were reversed. We found that cocaine-
experienced rats were slower to adjust responding for large rewards following
a state change as compared to sucrose controls. This behavioral change was
accompanied by differences in state encoding by DMS MSNs and FSIs. Prior to
odor onset, MSNs in the cocaine-experienced group exhibited decreased trial
type classification accuracy, suggesting a loss of state representation relative
to sucrose controls. However, following odor onset, FSIs in the cocaine group
displayed increased trial type classification accuracy, demonstrating enhanced
outcome representation. Together, these results indicate that DMS state
encoding is disrupted by cocaine experience. These findings are consistent with
a role for DMS cell populations in the regulation of behavioral flexibility and
suggest that alterations in task encoding may contribute to the poor decision-
making observed in individuals following exposure to drugs of abuse.

M6. Ventral Tegmental Area Glutamate Neurons Drive

Reinforcement Absent of Dopamine Co-Release
Vivien Zell*, Nick Hollon, Thomas Steinkellner, Shelley Warlow, Lauren Faget,
Larry Zweifel, Xin Jin, Thomas Hnasko
Like ventral tegmental area (VTA) dopamine (DA) neurons, we and
others have shown that activity of VTA glutamate neurons can support
positive reinforcement. However, a subset of VTA neurons co-release
both DA and glutamate, and DA release may be responsible for behavioral
reinforcement induced by activity of VTA glutamate neurons. To test this,
we used optogenetics to stimulate VTA glutamate neurons in which tyrosine
hydroxylase (TH), the rate-limiting enzyme in DA biosynthesis, was
conditionally ablated using either a novel mouse model or a CRISPR-Cas9-
based approach. These manipulations led to a loss of DA release evoked by
VTA glutamate neuron stimulation in the nucleus accumbens (NAc), while
glutamate neurotransmission remained intact. Despite the ablation of this
DA signal, optogenetic activation of VTA glutamate cell bodies or terminal
fibers in the NAc were both sufficient to support reinforcement in operant
behavioral assays. These results strongly suggest that glutamate release from
VTA terminals in the NAc is sufficient to promote reinforcement independent
of DA co-release, establishing a new circuit mechanism by which VTA activity
can influence reward-seeking behaviors.

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M7. Perineuronal Net Degradation Alters Cocaine
Reinstatement and Intrinsic Properties of Fast-Spiking
Interneurons in the Rat Medial Prefrontal Cortex
Emily Jorgensen*, Jake Aadland, Arianna Tourtellot, Tarver Boyce, Travis Brown
Our laboratory is interested in the molecular underpinnings that mediate
pervasive drug memories. Perineuronal nets (PNNs) are specialized
extracellular matrix structures primarily surrounding parvalbumin-containing
fast-spiking interneurons (FSI). Our research group previously published that
removal of PNNs within the medial prefrontal cortex (PFC) attenuates cocaine-
induced reinstatement of cocaine-conditioned place preference (cocaine-CPP)
and increases the firing rate of pyramidal neurons within the prelimbic PFC.
Our on-going research suggests that PNNs have a time-dependent effect on
modulating firing activity of FSIs to influence pyramidal neuron activity. Rats
underwent cocaine-CPP training and extinction. After meeting extinction
criteria, rats were microinjected into the prelimbic PFC 3d prior to cocaine-
induced reinstatement with either vehicle or chondroitinase ABC (ch-ABC) to
degrade PNNs. This procedure has shown to previously reduce cocaine-CPP.
2 hr following reinstatement, brain slices containing the mPFC were prepared
for whole-cell electrophysiological recordings. PNN degradation resulted in an
attenuation in the number of current-induced action potentials (APs) (vehicle:
99.0±7.31; ch-ABC: 53.33±1.43). In addition, we found significant changes
in both the halfwidth and afterhyperpolarization potential (AHP) of APs in
FSIs following ch-ABC treatment when compared to controls. Differences
in these specific intrinsic properties suggest that there could be alterations in
the currents responsible for the AHP and halfwidth. Current experiments are
investigating the role of slow conductance potassium channels in these intrinsic
differences. Furthermore, we are examining if PNN degradation alone affects
intrinsic excitability and synaptic transmission within the mPFC. Through this
work, we aim to further identify how PNNs are altering intrinsic and synaptic
transmission following cocaine-associated learning, which contributes to
persistent drug craving.

M8. Nucleus Accumbens Cholinergic Interneurons Drive

Dopamine Release During Motivated Approach
Joshua Berke*, Ali Mohebi
The mesolimbic dopamine pathway is critically involved in both learning
from past rewards, and motivation to work for future rewards. How dopamine
achieves these distinct functions is not fully known. Learning is thought to
involve bursts of dopamine cell spikes encoding prediction errors. Separately,
many groups including ours have observed ramps in accumbens dopamine
release, that accompany motivated approach behaviors and may encode

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reward expectation (value; Mohebi et al. Nature 2019; Hamid et al. Nat Neuro
2016). Surprisingly, value-related changes in accumbens dopamine release
occur without any change in spiking of VTA dopamine cells. We hypothesized
that motivational functions involve local regulation of release via receptors
on dopamine terminals. A candidate mechanism involves striatal cholinergic
interneurons (CINs): in brain slices, CIN stimulation evokes dopamine release
via nicotinic receptors.
We first established that this mechanism operates in awake, freely-moving
rats. We expressed ChR2 selectively in accumbens CINs, and stimulated these
neurons while monitoring dopamine release through the same optic fiber using
the red-shifted dopamine sensor RdLight1 (created by [Link], [Link]).
We observed a robust increase in dopamine, that scaled with the duration and
intensity of stimulation (n=4 fibers, 2 rats). Next, we examined whether the
natural activity dynamics of CINs can account for value-related dopamine
release. Using fiber photometry and the calcium indicator GCaMP6f we
observed rapid increases in CIN activity during motivated approach (n=8 fibers,
5 rats), mirroring the dopamine dynamics that cannot be accounted for by VTA
dopamine cell firing. These results support the hypothesis that motivation-
related changes in accumbens dopamine release are locally controlled by CINs.

M9. Delineating the Molecular Architecture of the

Dopaminergic Presynapse by Super-Resolution
Microscopy
Ulrik Gether*, Matthew Lycas, Jonatan Støier, Søren Heide Jørgensen, Daryl
Guthrie, Luke Lavis, Andreas Sørensen, Amy Newman, Freja Herborg
The dopaminergic presynapse consists of a unique repertoire of molecular
components of which some are unique to dopaminergic or monoaminergic
neurons while others make up generalized synaptic features. Indeed, processes
in the presynapse that govern dopamine (DA) storage, release and clearance
can modulate DA’s sphere of influence in target structures and may constitute
paths upon which dopaminergic dysfunction in disease converges into distinct
patterns of synaptic deficits. Single-molecule super-resolution microscopy
techniques, such as direct stochastic optical reconstruction microscopy
(dSTORM), has brought the advantages of fluorescence microscopy together
with a resolving power approaching that of EM, making super-resolution an
unprecedented tool for discovering structural correlates for synaptic function.
Recently, we have performed comprehensive super-resolution analyses of the
dopamine transporter. Our studies revealed how DAT moves in and out of
cholesterol-enriched nanodomain in presynaptic release sites of dopaminergic
neurons in a manner dependent on neuronal activity. Brief stimulation of
NMDA receptors in dopaminergic neurons, for example, caused Ca2+-
dependent dispersing of DAT nanoclusters but not of other key membrane

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proteins in the DAT presynapse. In contrast, brief stimulation with the
amphetamine, did not affect DAT distribution but elicited surprising changes
in the nanodomain distribution of other molecular components belonging
to the synaptic release machinery. The data demonstrate how application of
super-resolution microscopy in quantitative manner can visualize dynamic
architectural alterations in the presynapse that might be of critical importance
not only for synaptic function but also for drug responses and even diseased
states within the dopaminergic system.

M10. Extended-Release Injectable Naltrexone Before vs.

After Reentry for Opioid Addicted Prisoners
George Woody*
Background: Correctional facilities have a high prevalence of persons with
opioid use disorders. Usual treatment in the U.S. is clonidine detoxification
and referral to treatment at reentry. Few offer evidence-based medicine for
opioid use disorders and relapse with overdose death after reentry is common.
Extended-release injectable naltrexone (XR-NTX) might improve outcomes,
particularly if given before reentry. Methods: Consenting, detoxified, opioid
addicted prisoners in the Philadelphia county jail were randomized to receive
XR-NTX before reentry (BR) or after reentry (AR) and offered monthly
XR-NTX, weekly counseling, and weekly to monthly outcome assessments to
month 6. PRIMARY Outcome: relapse during the first 3 months after reentry
determined by 10 or more days of self-reported opioid use, withdrawal, and/
or two or more opioid positive urine tests within a 4-week period. Secondary
outcomes: XR-NTX doses received, overdoses, overdoses and overdose deaths,
reincarceration. Results: 422 prisoners expressed interest over 18 months
of recruitment, met admission criteria and consented, 86 were released to
outpatient treatment. Non-relapse by month 3was 39.5% in BR vs. 25% in
AR (p=0.20). BR patients remained in treatment longer and received more
XR-NTX than AR patients due to higher rates of receipt of the first (100%)
and return for the second injection (50%). 2BR patients had non-fatal ODs vs
6 AR patients. There were 4 OD deaths, 3 in AR, two within days of reentry.
All ODs were in patients that never started XR-NTX or started and dropped
out. 9 BR and 10 AR patients were receiving XR-NTX at month 4. Fifty were
re-incarcerated within the 28 months of study recruitment, treatment and
follow up, 28 in BR, 22 in AR (p=0.01). Conclusions: Some opioid addicted
prisoners are interested in XR-NTX and much more likely to receive it if
administered before reentry. Starting it BR did not reduce relapse over 3
months after reentry. The apparent OD protection associated with XR-NTX
adherence is consistent with its pharmacology and data from other recent
studies. Limitations: High levels of dropout, particularly in AR patients, with
reliance on self-reports for the primary and most secondary outcomes.

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M11. GluA1 Expression in Cortical-Accumbal Circuitry of
Differentially Reared Rats
Margaret Gill*, Adam Lundquist, Frank Pignone, Dylan Laux, Alexa Zimbelman,
Michael Stefanik
Early environmental experience impacts susceptibility to drug abuse later in
life. Rearing rats in enriched (EC) or impoverished (IC) conditions results in
rearing-induced neurobiological, neurochemical, and behavioral changes. In
particular, rats reared in an enriched condition (EC) following weaning exhibit
a protective effect, as EC rats are less reactant to the rewarding properties
of psychostimulant drugs at low doses, and self-administer less drug than
rats reared in an impoverished condition. Previous work implicates nucleus
accumbens (NA) GluA1 in cocaine self-administration and reinstatement, and
prelimbic cortex GluA1 in extinction. Based on this previous research, and work
in our own lab showing attenuated drug seeking behavior in IC rats infused with
an AMPA positive allosteric modulator into the infralimbic cortex (IL), the
current study sought to determine if GluA1 expression is differentially altered in
the prelimbic cortex (PL), IL and NA of EC and IC rats, following cue-induced
reinstatement. Rats were reared in either EC or IC environments for 30 days,
and then trained to self-administer cocaine using a 2-hr self-administration
model (FR1; 4.0 mg/mL cocaine dose). Following extinction, rats underwent
cue-induced reinstatement, and brains were immediately extracted from the
rats. Tissue was processed and immunoblotting was used to quantify GluA1
protein levels in the NA, PL, and IL. Immunoblotting results reveal that EC rats
display greater GluA1 expression in the PL compared to IC rats, while there are
no differences in GluA1 expression in the IL and NA. This suggests that AMPA
receptors levels in cortical areas are altered by differential rearing, and this may
be a mechanism by which EC rats are protected from drug-taking behavior.

M12. Validation of Fos-mRFP Rats to Map Neuronal

Ensembles Underlying Reward-Related Behaviors
Katherine Savell*, Rajtarun Madangopal, Leslie Whitaker, Jae Choi, Elise Van Leer,
Sophia Weber, Veronica Lennon, Megan Brenner, Lauren Komer, F. Javier Rubio,
Bruce Hope
Learned associations are thought to be encoded by sparsely distributed
populations of activated neurons called ‘neuronal ensembles’. Sustained
neuronal activity triggers cellular signaling cascades which result in the
induction of immediate early genes (e.g. Fos, Arc, Egr1) that are used as
markers to identify neuronal ensembles. Fos-expressing ensembles have
recently been shown to mediate a number of reward-related behaviors. Rats
are commonly used to model complex behavioral and cognitive processes and
are often viewed to have more relevance as a model for human disease, but
limited transgenics exist due to difficulties in genetic manipulation. Here, we

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characterize reward-related regions of a previously generated transgenic rat line
that expresses a monomeric red fluorescent protein (mRFP) under the control
of the Fos promoter to label Fos-expressing ensemble neurons. We tracked
the time-course of Fos and mRFP expression in the infralimbic and prelimbic
subregions of the prefrontal cortex after novel context exposure. The overlap
between mRFP- and Fos-positive cells was consistently high and the proportion
of mRFP-only cells consistently low across all timepoints investigated. Our
results indicate that the spatiotemporal expression of mRFP reliably matches
that of Fos in this transgenic rat line i.e. mRFP expression is specific to neurons
that express Fos. Ongoing work aims to validate transcriptional dynamics of
Fos and mRFP expression through FACS and the role of cellular signaling
cascades in vitro. The Fos-mRFP transgenic rat allows longitudinal investigation
of Fos-expressing neurons in vivo and can be used in conjunction with green
fluorescence-based indicators to investigate properties of neuronal ensembles in
reward-relevant behaviors.

M13. Reward Expectation Differentially Drives

Dopaminergic Responses Across Striatal Sub-Regions
Christopher Donahue*, Benjamin Margoin, Jacob Nadel, Aphroditi Mamaligas,
Anatol Kreitzer
Dopamine is thought to play a central role in learning and motivation through
its influence on striatal circuitry. Recent work has demonstrated that striatal
dopamine signaling is much more diverse that previously thought, with
movement and reward signals differing dramatically across different striatal sub-
regions. However, the functional role of these heterogeneous responses have
not been characterized in detail. To investigate this, we trained mice to perform
two complementary tasks in which we systematically manipulated the amount
of effort required to obtain reward. In the first task (fixed ratio), the number of
movements required for reward delivery was manipulated in blocks so that the
amount of effort required was predictable. In the second task (variable ratio),
the number of movements were randomized and could not be predicted. We
found that movements became successively faster as the animals progressed
through the nose-poke sequence only in the fixed ratio task, demonstrating that
knowledge about reward proximity invigorated their upcoming movements.
We expressed a dopamine sensor (dLight 1.1) bilaterally across three different
striatal sub-regions (dorsomedial, dorsolateral, and ventral striatum) and
recorded fluorescence while animals performed each task. The magnitude of
movement-evoked dopamine release systematically increased as animals got
closer to reward in all sub-regions in the fixed ratio task, but not in the variable
ratio task. Next, we compared activity across hemispheres and found that both
movement and reward signaling were more lateralized in the dorsomedial
striatum compared to other sub-regions. Together, our results demonstrate

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that striatal dopamine is robustly modulated by reward expectation, and that
dopamine in the dorsomedial striatum may play a unique role in directing
action towards locations that are more likely to lead to reward.

M14. Investigating the Role of TrkB in Value-Based

Decision Making
Ellen Woon*, Ari Peluso, Shannon Gourley
Value-based decision making, referring to selecting actions with the expectation
they will be rewarded with valued outcomes, relies on the medial orbitofrontal
cortex (mOFC). One molecular candidate that likely sustains value-based
decision-making is Brain-derived Neurotrophic Factor (BDNF). Given that
BDNF is subject to anterograde and retrograde transport, however, where
(and when) BDNF binding is necessary for optimal decision making remains
unclear. Here, we administered an antagonist against the high-affinity BDNF
receptor, tyrosine/tropomyosin receptor kinase B (TrkB), during the encoding
or retrieval of new memories regarding food value. Inhibiting TrkB activity
during the encoding, but not the retrieval, of new memory regarding food value
impaired value-based action selection. Then, to determine where TrkB activity
was necessary for value-based decision making, we overexpressed an inactive
isoform of TrkB, TrkB.t1, in the mOFC or basolateral amygdala (BLA), which
shares connections with the mOFC. TrkB.t1 overexpression in both regions
impeded optimal response selection, but in dissociable manners. Specifically,
TrkB activity in the mOFC is involved in value-based action when action
outcomes are not observable and must be inferred. Meanwhile, TrkB activity
in the BLA is necessary for value-based action regardless of whether outcomes
are observable or action selection requires inference and prediction about the
future. These patterns suggest that neurotrophin activity in the BLA is necessary
for optimal action selection strategies, potentially by conveying outcome value
information to other structures, such as the mOFC, with more specialized
functions.

M15. Prefrontal Neuronal Encoding of Threat-Related

Stimuli Across the Estrous Cycle
Marieke Gilmartin*, Matthew Herbst, Matthew LaViola, Robert Twining
The association of a neutral conditional stimulus (CS) and aversive footshock
unconditional stimulus (UCS) that are separated in time, as in trace fear
conditioning, requires activity in the prelimbic area (PL) of the medial
prefrontal cortex. We have previously shown that a subset of PL cells shows
sustained firing in response to the CS and that optogenetic silencing of
prefrontal activity during the trace interval between the cue and shock prevents
learning (Gilmartin & McEchron, 2005; Gilmartin et al., 2013). Recently, we

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have uncovered sex differences in the prefrontal cortical contribution to trace
conditioning (Kirry et al., 2018; 2019). In one study, the estrous cycle gated
the memory-impairing effects of a muscarinic antagonist in the PL (Kirry et
al., 2019), which suggested that circulating ovarian hormones may modulate
prefrontal encoding during aversive learning. Here we recorded neuronal
activity in the medial prefrontal cortex during the acquisition and extinction of
trace fear conditioning. The estrous cycle of female Long-Evans rats was tracked
for two cycles and then half of the rats started training on the day of proestrus
and the other half started training on the day of metestrus. Training occurred
over two days and testing in a shifted context occurred when the rats returned
to their initial training cycle stage. Initial results (n = 6/group) have revealed
similar sustained activation to the CS but divergent encoding of the UCS
during day 1 of training. Proestrus females exhibited a robust increase in firing
in response to the UCS, and metestrus females exhibited a modest response.
Neuronal encoding on day 2 of training and subsequent conditional fear to the
cue and context at test was similar between groups. Follow-up experiments
will determine whether these divergent patterns of PL encoding of the UCS
mediate cycle differences in cued fear retention after only one day of training,
that can be overcome with additional training. These findings will reveal how
prefrontal encoding of threat-related stimuli does and does not change across
the estrous cycle, shedding light on how neuromodulation of prefrontal activity
differentially affects the formation of fear memories between sexes and across
the estrous cycle.

M16. Temporal Dynamics of Spatial Information Encoding

Within Retrosplenial Cortex
Megha Sehgal*, Sunaina Martin, Asli Peckan, Daniel Aharoni, Shan Huang, Ayal
Lavi, Alcino Silva
Memories are dynamic in nature and a cohesive representation of the world
requires memories to be linked with other related memories. Our laboratory
has recently demonstrated that the overlap between the hippocampal CA1
ensembles encoding two contextual memories acquired close in time mediates
memory linking, whereby the recall of one memory can lead to the recall of
another memory (Cai et al. 2016). Retrosplenial cortex or RSC is another
brain structure that is critical for contextual learning and memory. It is unclear
whether memory linking is a specific property of CA1 ensembles or whether
other brain regions involved in contextual processing also display this pattern
of neuronal overlap between ensembles encoding memories acquired close in
time. We addressed this question by investigating the overlap in RSC neuronal
ensembles encoding contextual memories at varying time intervals. Using
head-mounted fluorescent microscopes (miniscopes), we imaged GCaMP6f-
meadiated calcium dynamics in retrosplenial cortical neurons while the
mice explored distinct contexts. We found greater overlap in the neuronal

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ensemble activated in response to two distinct contexts when the contexts
were explored 5-hours vs. 7-days apart. These data suggest that the RSC could
mediate temporal memory linking by recruiting a shared neuronal ensemble
for memories encoded within a day. Furthermore, to understand whether such
ensemble overlap was driven by neurons encoding spatial information, we
performed linear track experiments where RSC calcium transients were imaged
using miniscopes. We found that a subset of RSC cells (~35%) displayed place
cell like dynamics. Furthermore, the same cells could be followed over repeated
linear track sessions. These cells displayed stable firing patterns indicating
retention of spatial information over days. Interestingly, the reactivation of RSC
place cells over subsequent linear track sessions was similar to that of RSC non-
place cells indicating that RSC place cells follow similar temporal dynamics as
the non-place cells. All together our data indicate that co-allocation of neuronal
ensembles encoding temporally proximate contextual memories may be a
general mechanism of memory linking across the brain regions that process
spatial and contextual information.

M17. Making Sense of Computational Psychiatry

Helmut Strey*, Lilianne Mujica-Parodi
In clinical neuroscience we often speak of constructing “models.” Here we
try to make sense of what such a claim might mean, starting with the most
fundamental question: “What is (and isn’t) a model?”. We then discuss, in a
concrete measurable sense, what it means for a model to be useful. In so doing,
we first identify the added value that a computational model can provide, in
the context of accuracy and power. We then present the limitations of standard
statistical methods and provide suggestions for how we can expand the
explanatory power of our analyses. Finally, we address the problem of model
building—suggesting ways in which generative models can escape the potential
for cognitive biases imposed by classical hypothesis-driven research, exploiting
deep systems-level information contained within neuroimaging data to advance
our understanding of psychiatric neuroscience.
To illustrate our approach, we will present a stochastical model for fMRI
measurements of the human resting state and compare it quantitatively to other
theoretical models.

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M18. Neural Precursor Cell Derived Brain-Like Tissue
Induces the Formation of Long-Range Connections in the
Adult Brain
Gretchen Greene*, Nikorn Pothayee, Dragan Maric, Stephen Dodd, Alan Koretsky
Neurodegeneration is a hallmark of many neurological disorders, stroke, and
traumatic brain injury. However, the central nervous system (CNS) generally
lacks the ability to regenerate damaged neurons, and therefore treatments
that repair and promote neuronal growth are highly desirable. Neural stem
cell transplantation has potential to replace neuronal tissue lost due to injury
or disease, yet current research has not evaluated the ability for long distance
axonal ingrowth originating from the host brain projecting to graft, which
may be critical for functional recovery and repair. Previously we have shown
that early-stage neural precursor cells (NPCs) implanted in the cerebrospinal
fluid of adult rats develop into a brain-like tissue (BLT) that is integrated with
the host brain. The NPCs differentiate into neurons and astrocytes forming a
tissue growth that is vascularized by the host. Additionally, host GABAergic
interneurons and microglia migrate into the BLT and we find oligodendrocytes
originating from both the host brain and the transplanted NPCs. In this study,
we implanted NPCs near the subventricular zone of 3 week and 4 month old
host rats. The NPCs developed into an integrated brain-like tissue in both 3
week and 4 month old host brains and neurons derived from the implanted
NPCs sent long range axonal projections along the rostral-migratory stream
into the host olfactory bulb. Strikingly, the host brain developed long-distance
axons projecting into the BLT. Through tracing with retrograde AAV and
Fluorogold, we have found that the host axons innervating the new tissue
growth originate in the prefrontal cortex. Additionally, we see that neurons
derived from the transplanted precursor cells project back to the prefrontal
cortex suggesting a level of reciprocal connectivity. This demonstrates the ability
of transplanted NPCs to integrate with the mature brain circuitry. The potential
of NPCs to form integrated neuronal tissue and induce bidirectional long-range
connectivity may have implications for CNS regenerative medicine and open up
questions about axonal plasticity in post-critical period brain development.

M19. Sex Differences in Body Composition but Not

Neuromuscular Function Following Long-Term,
Doxycycline-Induced Reduction in Circulating Levels of
Myostatin in Mice
Sonsoles de Lacalle*, Dallin Tavoian, Sophia Mort, W. David Arnold
Age-related declines in muscle function result from changes in muscle structure
and contractile properties, as well as from neural adaptations. Blocking
myostatin (MSTN) to drive muscle growth is one potential therapeutic

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approach. While the effects of myostatin depletion on muscle characteristics
are well established, we have very little understanding of its effects on the neural
system. Here we assess the effects of long-term, post-developmental myostatin
reduction on motor unit characteristics and body composition in aging mice.
We used male and female mice containing a tetracycline(DOX)-inducible
system to delete MSTN in skeletal muscle. Starting at 12 months of age,
half of the mice were administered DOX through their chow for 1 year.
During that time, we measured food intake, body composition, and hindlimb
electromyographic responses.
DOX-induced MSTN reduction had no effect on motor unit properties for
either sex, but significant age-dependent declines in motor unit number
occurred in all mice. Treatment with DOX induced different changes in body
composition between sexes. All female mice increased in total, lean and fat
mass, but DOX-treated female mice experienced a significantly larger increase
in lean mass than controls. All male mice also increased total and lean mass, but
administration of DOX had no effect. Additionally, DOX-treated male mice
maintained their fat mass at baseline levels, while the control group experienced
a significant increase from baseline and compared to the DOX treated group.
Our results show that long-term administration of DOX results in body
composition adaptations that are distinctive between male and female mice,
and that the effects of MSTN reduction are most pronounced during the first
three months of treatment. We also report that age-related changes in motor
unit number are not offset by reduced MSTN levels, despite increased lean mass
exhibited by female mice.

M20. The Role of Inflammation Markers in Functional

Cortical Activation Deficits During Manual Tasks in
Postmenopausal Women With Type II Diabetes
Stacey Gorniak*, Arturo Hernandez, Luca Pollonini
The overall aim of this project was to evaluate the relationship among outcomes
in manual sensorimotor behavior, cortical activation, and health state markers
in postmenopausal females with Type II Diabetes (DM). Our recent studies
have shown that adults with DM experience declines manual sensorimotor
function that are not associated with a diagnosis of diabetic peripheral
neuropathy (DPN); however, it is not clear if cortical deficits are responsible.
Currently, no specific consistent structural deficits have been identified as a
cause to motor deficits in persons with DM. The reported behavioral deficits
may be exacerbated in older adult females with DM, who are at the highest
risk of cardiovascular decline, as DM is considered a cardiovascular disease.
Twenty-one (21) community-dwelling DM patients (age = 65 ± 6 years,
A1c = 7.5 ± 1.1) and twenty-one (21) age- and sex-matched healthy controls
(age = 66 ± 6 years, A1c = 5.4 ± 0.3) were recruited and evaluated in this

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cross-sectional study. Tactile detection and motor performance were evaluated
while study participants donned cortical functional near-infrared spectroscopy
devices (f NIRS) in one testing session. Tactile detection was evaluated via
fingertip vibration; motor performance was evaluated by isometric pinch force
production at two force levels using the thumb and index finger of the right
hand. Bilateral cortical regions of interest (ROIs) included: PFC, SMA, M1,
S1, and Brodmann area 40. Health state, metabolic, and menopausal status data
were collected. No differences in tactile function were found between the two
groups. No between group ROI activation differences were found in the tactile
stimulation task. Deficits in sensory function and fine motor performance
were found in the DM group (p < 0.01). Reduced HbO responses were found
across all ROIs in the DM group (p < 0.05) during performance of the lower
force level motor task. Group-based ROI activations did not show significant
differences during the high force production task. Reduced HbO was associated
with: (a) worsened motor function, and (2) worsened health state indices.
These data are the first to indicate functional cortical deficits in postmenopausal
females with DM. This suggests a potential combination of central deficits and
inflammation leading to functional declines with aging and DM.

M21. Repeated Mild Traumatic Brain Injury Impairs

the Functional Integrity of the Locus Coeruleus-
Noradrenergic System
Barry Waterhouse, Alexis Foschini, Leah Horvat, Doug Fox, James Grininas, David
Devilbiss*
Mild traumatic brain injury (mTBI) affects approximately 1.7-3.8 million
Americans each year. TBI is a complex pathophysiological process resulting
in behavioral and cognitive deficits including impaired arousal, attention,
decision-making, and other executive functions. Although symptoms generally
resolve within three months after a single insult, repetitive mild injuries may
produce cumulative effects, increase the susceptibility for further mTBI,
and increase the likelihood of long-term cognitive deficits. Catecholamine
systems, including the locus coeruleus (LC) -norepinephrine (NE) pathway,
are critical regulators of the higher executive processes affected by TBI.
Impaired LC-NE function is implicated in the pathogenesis of the cognitive and
neuropsychiatric symptoms following moderate to severe TBI. Yet, the effects
of mild TBI and repetitive TBI on catecholamine system function are poorly
understood. Methylphenidate (MPH) and other psychostimulants are used to
improve normal executive processes and to treat attention deficit hyperactivity
disorder (ADHD). However, limited and inconsistent findings exist on the
efficacy of MPH for treating the cognitive impairments following mild TBI
due to small sample sizes, poor patient stratification, and limited dose ranges.
The objectives of the current study were to determine the extent of LC-NE

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functional impairments following repetitive mild TBI and to assess its response
to a challenge dose of MPH. We found a reduction in dopamine-β-hydroxylase
(DBH) and norepinephrine transporter (NET) immunoreactivity within the
prefrontal regions of the rat brain following repetitive mild TBI. Additionally,
baseline LC neuron discharge patterns, NE efflux within the prefrontal cortex,
and the response of the LC-NE system to the MPH challenge were significantly
altered after repetitive mild TBI. These findings provide critical insight into the
sensitivity of catecholamine fibers to repeated mild TBI and support for the role
of noradrenergic fiber injury in the cognitive deficits resulting from repeated
injury.

M22. Perampanel Treatment of Benzodiazepine-

Refractory Status Epilepticus
Jerome Niquet, Ireri Franco Estrada, Claude Wasterlain*
Objective: To assess the effectiveness of perampanel, a specific antagonist for
AMPA-type glutamate receptors, as a second-line treatment of benzodiazepine-
unresponsive Status Epilepticus (SE).
Background: SE responds poorly to benzodiazepines, especially when
treatment is delayed. Experimental data show that SE causes an early
maladaptive internalization of synaptic GABAA receptors, which may explain
benzodiazepine pharmacoresistance, along with a migration of NMDA and
AMPA receptors (AMPAR) towards synapses, increasing glutamatergic
excitation. Topiramate, an AMPAR antagonist, is often effective in refractory
SE, and the stronger AMPAR antagonist perampanel deserves evaluation in the
treatment of SE.
Design/Methods: SE was induced in adult male Sprague-Dawley rats by high-
dose lithium/pilocarpine, and EEG/video was recorded for 18 hrs. Midazolam
(1 mg/kg; ip) was injected 40 min after SE onset. Perampanel (0.5, 1 or 2 mg/
kg, ip) or valproate (270 mg/kg) was injected 20 min following midazolam if SE
continued.
Results: During the first hour following treatment with perampanel 2 mg/kg
(−84 ± 314; p<0.0001) or 1 mg/kg (170 ± 410; p<0.01), but not valproate 270
mg/kg (453 ± 393), EEG power was decreased compared to midazolam alone
(671 ± 208). Perampanel 2 mg/kg (median = -514; interquartile range: -1072
to -73; p<0.001) or 1 mg/kg (207; -675 to 758; p<0.05), but not valproate
270 mg/kg (1027; 396 to 3346), also significantly reduced the EEG power
integral over the 6 h posttreatment when compared to midazolam alone (2407;
1557 to 3813). In addition, after perampanel 2 mg/kg the time needed for
EEG amplitude to decline to twice the pre-seizure baseline (median = 11 min;
interquartile range: 6 min – 31 min), was reduced compared to midazolam (42
min; 33-77 min); p < 0.05), suggesting earlier SE termination.

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Conclusions: Perampanel is potent in stopping midazolam-refractory SE even
when given 60 min following SE onset in this animal model of severe SE.

M23. Projectile Concussive Impact as a Preclinical Model

for Traumatic Brain Injury
Lindsay Michalovicz*, Kimberly Kelly, James O’Callaghan
Traumatic brain injury (TBI) is as a major cause of death and disability
experienced by nearly 3 million people per year. These injuries can be
experienced in any environment, e.g. work or home, and can result from falls,
vehicular accidents, or from being struck by or against an object. While TBIs
can be severe and/or fatal, the majority of injuries are considered to be mild.
However, even mild TBI has the potential to have long-lasting neurological
effects including headaches, cognitive or memory impairments, mood
dysfunction, and fatigue. By using animal models of TBI, we can investigate
the underlying pathophysiology that can lead to neurological dysfunction
in the absence of serious trauma (i.e. penetrating injuries). Here, we used a
projectile concussive impact (PCI) model of mild TBI developed at Walter
Reed Army Institute of Research, where a ball bearing is propelled at the head
by air pressure. While several studies using PCI have employed a helmet to
mitigate direct damage from impact, we needed to utilize a non-helmeted
model of PCI-induced TBI in order to evaluate the protective nature of different
helmet materials for the mitigation of work-related TBI. Adult male Sprague-
Dawley rats were used to evaluate neurobehavioral, neuroinflammatory and
neural damage end points up to 72 hours following TBI using different types
of ball bearing. Animals that received TBI using either aluminum or steel ball
bearings took approximately 1.7 and 7.3 times longer to recover from anesthesia
compared to sham controls. Moreover, while rats impacted with aluminum were
behaviorally normal even 1 hour following TBI, those impacted with the steel
ball bearing had an impaired neurobehavioral score for up to 24 hours post-TBI
which correlated with the presence of subdural hematoma and significantly
higher markers of neuroinflammation. This non-helmeted variation of the PCI
model is capable of producing a TBI which can be used for the future evaluation
of helmet materials.

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M24. CaMKII Versus DAPK1 Binding to GluN2B in
Ischemic Neuronal Cell Death After Resuscitation From
Cardiac Arrest
Olivia Buonarati*, Sarah Cook, Dayton Goodell, Nicholas Chalmers, Nicole
Rumian, Jonathan Tullis, Susana Restrepo, Steven Coultrap, Nidia Quillinan, Paco
Herson, Ulli Bayer
DAPK1 binding to GluN2B-containing NMDA receptors was prominently
reported to mediate ischemic cell death in vivo. DAPK1 and CaMKII bind
to the same GluN2B region, and their binding is mutually exclusive. Here,
we show that mutating the binding region on GluN2B (L1298A/R1300Q)
protected against neuronal cell death induced by cardiac arrest followed by
resuscitation. Importantly, the GluN2B mutation selectively abolished only
CaMKII but not DAPK1 binding. During ischemic or excitotoxic insults,
CaMKII further accumulated at excitatory synapses, and this accumulation
was mediated by GluN2B binding. Interestingly, extra-synaptic GluN2B
decreased after ischemia, but its relative association with DAPK1 increased.
Thus, ischemic neuronal death requires CaMKII binding to synaptic GluN2B,
whereas any potential role for DAPK1 binding is restricted to a different, likely
extra-synaptic population of GluN2B.

M25. Data Archive for the BRAIN Initiative (DABI)

Rachael Garner, Nader Pouratian, Arthur Toga, Dominique Duncan*
In the field of invasive neurophysiology, studies are costly and prohibitive, as
patients are not often willing to undergo neurosurgery for experimental devices
or elective experiments, so data sharing is of great importance. For example,
data sharing may allow individual researchers to generate statistical power
to prove an experimental device is safe and effective and identify candidate
subjects, target sites, and stimulation parameters.
Data Archive for the BRAIN Initiative (DABI) fills this scientific need by
providing a centralized database for human invasive neurophysiology data –
clinical, imaging, pathology, demographics, behavioral, and electrophysiology.
The archive ingests, harmonizes, aggregates, stores, visualizes, and disseminates
multimodal data (Fig.1). DABI allows data providers to organize and analyze
data in one platform and also encourages multi-site investigations. Investigators
can build multi-site cohorts based on filters, including gender, diagnosis, age,
recording location, and data modalities available (Fig.2). Data trends and
correlations can then be calculated in DABI without downloading raw data.
Integrated software and analytics include image visualization, quality control,
LONI Pipeline, Jupyter, R Analysis and Visualization of intracranial EEG Data
(RAVE), and a variety of statistical tests.

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Investigators maintain complete ownership and control of their data.
Unaffiliated users must be granted access from PIs to download raw data or
conduct analysis using DABI’s built-in analytics.
DABI is a platform of networked and centralized web-accessible data archives
to capture, store, and curate invasive human neurophysiological data and
make them broadly available and accessible to the scientific community for
furthering neuroscience research. Moreover, DABI also alleviates the burden on
investigators to organize and ingest their data by harmonizing and storing the
vast array of data collected in invasive human recording studies.

M26. Characterization of a Novel Allelic Variant of the

Human Dopamine D2 Receptor
Kim Neve*, Dayana Rodriguez, Michelle Kielhold, Brooks Robinson, Alec Condon,
Naeem Asad, Timothy Dore, John Williams
A novel DRD2 variant has been identified encoding a D2 receptor (D2-Mut)
with an amino acid change in the third cytoplasmic loop. When transiently
expressed in HEK293 cells, the D2-Mut receptor density is about 35-40% of
D2-WT. We assessed arrestin recruitment, G protein activation, and stimulation
of cyclic AMP accumulation by D2-Mut. Maximal arrestin recruitment by
D2-Mut was ~half that of D2-WT, even when expressed at similar levels,
and was characterized by a faster decay, compared to D2-WT, and by almost
complete dependence on overexpression of GRK2. In contrast, quinpirole
dose-response curves for activation of Gαi by D2-Mut were left-shifted 5- to
7-fold compared to D2-WT, indicative of more efficient G protein activation.
Basal activation of G protein in HEK293 cells expressing D2-Mut was increased
by 30% of the maximal response to D2-WT, consistent with enhanced
constitutive (unliganded) activity. We also observed left-shifted dose-response
curves and increased basal activity for inhibition of forskolin-stimulated cyclic
AMP accumulation by D2-Mut. After AAV-mediated expression in dopamine
neurons of D2 autoreceptor knockout mice, both variants mediated synaptic
currents in response to release of endogenous dopamine, whether spontaneous
or elicited by electrical stimulation, and in response to iontophoretic dopamine,
but time-to-peak was slower and peak half-width was greater for D2-Mut.
Uncaging of photoactivated sulpiride (CyHQ-sulpiride) produced an apparent
inward current of about 10 pA in cells expressing D2-WT, consistent with
inhibition of a tonic GIRK current. CyHQ-sulpiride photolysis produced a
much larger inhibition of 60-70 pA in cells expressing D2-Mut. To determine
whether the sulpiride response reflected inverse agonism of constitutive activity
or antagonism of endogenous dopamine, slices were treated with reserpine 1
hr prior to recording. Reserpine-induced dopamine depletion abolished the
response to sulpiride in cells expressing D2-WT and greatly decreased the
response in cells expressing D2-Mut, consistent with our interpretation that

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D2-Mut exhibits modestly more constitutive activity and substantially greater
sensitivity to dopamine than D2-WT. Overall, D2-Mut is a G protein-biased
receptor with enhanced constitutive activity. (VA Merit Review)

M27. A Semi Mechanistic Pharmacokinetic Model to

Understand the Metabolic Conversion of Mitragynine to
7-Hydroxymitragynine
Abhisheak Sharma*, Tamara King, Shyam Kamble, Francisco León, Julius Hertin,
Till-Arved F. Ehrenhart, Christopher McCurdy, Bonnie Avery
Mitragynine, the major alkaloid of kratom (Mitragyna speciosa), is believed
to be predominantly responsible for kratom’s psychoactive effects. It has
been shown that mitragynine is metabolized to 7-hydroxymitragynine,
which is also a minor alkaloid of kratom, that is 13- and 46-fold more potent
than morphine and mitragynine, respectively. The potent kratom alkaloid,
7-hydroxymitragynine, also produces tolerance, cross-tolerance to morphine,
and physical dependence. Thus, it is necessary to understand the rate and
extent of metabolic conversion of mitragynine to 7-hydroxymitragynine.
Oral (20 mg/kg) and intravenous (2.5 mg/kg) pharmacokinetic studies of
mitragynine were performed in female Sprague Dawley rats (N=6, each),
and concentrations of both mitragynine and 7-hydroxymitragynine were
determined in plasma and brain samples using a validated ultra-performance
liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method.
Concentrations of mitragynine and 7-hydroxymitragynine in brain 24 h
post-dose were 325.6 ± 99.1 and 15. 6 ± 5.7 ng/g for orally and 62.9 ± 31.5
and 0.9 ± 0.1 ng/g for intravenously dosed rats. The percentage area under
curve (%AUC) of 7-hydroxymitragynine to mitragynine followed by oral and
intravenous administration of mitragynine was found to be 9.1 ± 0.3 and 3.3 ±
0.3%, respectively. A comparatively higher metabolic conversion of mitragynine
to 7-hydroxymitragynine following oral administration than intravenous route
can be attributed to the intestinal metabolism of mitragynine. Based on the
diagnostic plots, lowest Akaike’s information criterion (AIC) and Schwarz
criterion (SBC), a three-compartmental open model was found to be the best fit
for both oral and intravenous concentration-time data of mitragynine (Phoenix
NLME, version 6.3; Certara Inc, Missouri, USA). The pharmacokinetic model
of mitragynine was further extended to describe its metabolic conversion to
7-hydroxymitragynine (Figure 1). After successful fitting, both mitragynine
and 7-hydroxymitragynine concentration-time data, conversion coefficient of
the parent to the metabolite was found to be 0.04 ± 0.002 h-1. The developed
pharmacokinetic model can be further extended to predict human exposure of
7-hydroxymitragynine using basic allometric principles.

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M28. Can Axons Finding Their Way in Prefrontal Cortex in
Neurodevelopmental Disorders?
John Huguenard*, Tanya Weerakkody, Brielle Ferguson, Christopher Makinson
Autism Spectrum Disorder (ASD) is a complex heterogeneous
neurodevelopmental syndrome with genetic and environmental risk factors.
Infection during pregnancy is strongly implicated as an environmental factor,
with maternal immune activation (MIA) identified in the causative pathway.
However, a mechanistic understanding of MIA induced alterations in brain
function and accompanying social behavior remains elusive. Here, using a
mouse MIA model, we find in offspring a profound and persistent impairment
in the excitability of medial prefrontal cortex (mPFC) – a key locus of
social cognition and ASD pathology. Specifically, we find a novel structural
disorganization of the axon initial segment and blunted spike transmission
along the axon. Transcriptomic analysis identified L1cam deficiency as a
likely key mediator of the structural and functional impairments. Inactivation
of L1cam in mPFC reproduces impairment in social behavior. These results
demonstrate a fundamental alteration in the output of mPFC neurons in ASD.
Large-scale synaptic deficits in excitation and inhibition within the mPFC were
primarily attributed to reduced presynaptic activation of layer 5 pyramidal
neurons, which corresponded to defective action potential initiation in whole-
cell patch clamp recordings. In addition, orthodromic axonal spikes, as detected
by axon-attached recordings, were significantly attenuated in MIA offspring
and exhibited reduced propagation velocities. Finally, axon initial structure,
based on staining for Ankyrin-G was disrupted, show an anatomical basis for
altered axon function. Based on these results, we identify presynaptic axonal
excitability as a novel contributor to ASD-related mPFC dysfunction.

M29. Rare Genetic Variants in Monoamine Transports as a

Risk Factor for Neuropsychiatric Disease? Insights From a
Population Based Case-Control Sample
Freja Herborg*, Vivek Appadurai, Alfonso Demur, Thomas Werge, Ulrik Gether
The monoaminergic circuits of the brain have long been implicated in most of
the common neuropsychiatric diseases. Still, it is not clear if disease-relevant
circuit dysfunctions can originate in monoaminergic neurons and sensitise
individuals to develop neuropsychiatric disease. The monoamine transporters
(MAT) are selectively expressed in monoaminergic neurons and serve as
key regulators of monoaminergic neurotransmission and as principal targets
for neuropsychiatric therapeutics. Using exome sequencing data from 5554
controls and 14283 cases diagnosed with attention deficit hyperactivity
disorder, (ADHD, N=5040), autism spectrum disorder (ASD, N=5694),
schizophrenia (N=3686), depression (N=2967), or bipolar disorder (N=1528),

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we address if disruptive genetic variants in the MAT genes (SLC6A2/NET,
SLC6A3/DAT, SLC6A4/SERT, and SLC18A2/VMAT2) associate with
neuropsychiatric disease. We found a significant excess of both ‘loss of function’
(LoF) variant sites (P=0.013) and number of carriers (P=0.046), in patients
diagnosed with mental disorders. Moreover, analysis of disease associations
at single gene level, uncovered a complete absence of LoF variants in NET/
SLC6A2 in control individuals with resulting significant disease associations
between NET/SLCA2 and ASD, schizophrenia, depression and bipolar
disorder. A nominal significant disease association was also found for DAT/
SLC6A3 and ADHD. These findings provide new support to the monoamine
hypothesis of neuropsychiatric disease by directly linking inherited changes to
MAT function to an increased the risk of neuropsychiatric disease.

M30. Cocaine Actions on Cortico-Striatal Circuitry: A

Focus on Cholinergic Interneurons
Michael Authement*, J.H. Shin, Veronica Alvarez
Cholinergic interneurons (CINs) of the striatum are thought to play a critical
role in behavioral flexibility and dysfunction of CINs may underlie the
pathology of compulsive behaviors that are expressed in drug abuse. Although
CINs account for only 1% of striatal neurons, they are the major source of
acetylcholine in the striatum. Furthermore, recent studies have identified
another critical function of CINs: triggering dopamine release. Direct and
indirect activation of CINs through cortical and thalamic inputs can evoke
dopamine release independent of midbrain dopaminergic neuron firing.
Therefore, we hypothesize that if drugs of abuse have effects on CIN physiology,
they would not only affect the levels of acetylcholine in the striatum, but also
affect this novel form of striatal dopamine signaling. The central goal of this
study is to identify the mechanisms underlying the acute and chronic effects of
cocaine, a stimulant drug of abuse, on CIN activity and on synaptic inputs to
CINs. Specifically, we are focusing on glutamatergic inputs from the prefrontal
cortex (PFC) onto CINs based on the well-known role of the PFC in behavioral
flexibility and inhibitory control. Recordings from CINs in ex vivo brain slices
showed that cocaine potently and dose-dependently depressed excitatory
transmission from PFC inputs onto CINs. The mechanism underlying this
acute depression appeared to be presynaptic and was not blocked with the D2
dopamine receptor antagonist sulpiride. Cocaine increased the spontaneous
action potential firing in CINs by two-fold, and this effect was blocked with
a serotonin receptor antagonist, ketanserin, or D1/D5 dopamine receptor
antagonist, SCH-23390. After repeated administration of cocaine over a 5-day
period, the excitability of CINs was decreased and remained lower for up to 21
days after the last cocaine administration. Thus, while cocaine acutely increases
CIN firing, chronic exposure to cocaine produces a long-lasting depression

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of firing, a plasticity in the opposite direction. These studies are revealing
novel actions of cocaine on cortico-striatal circuitry that we speculate may
contribute to the loss of inhibitory control and the behavioral inflexibility that
characterizes compulsive cocaine use.

M31. Exploration of Posttranscriptional and Translational

Regulation in Depolarized Neuroblasts
Dylan Kiltschewskij, Murray Cairns*
Experience-dependent modification of synaptic structure and function are
driven by complex temporospatial patterns of mRNA translation. Although
the translational profiles of a subset of excitation-dependent mRNAs have
been determined, the global dynamics of translation and the functional
contribution of posttranscriptional regulatory factors, such as small non-
coding RNA, remain poorly understood. In the current study, we explored
excitation-sensitive patterns of translational activity by conducting ribosome
profiling on differentiated SH-SY5Y cells at several time points after repeated
K+ depolarization. This was carried out in conjunction with mRNA sequencing
to investigate whether modulation of mRNA translation matched underlying
profiles of mRNA abundance, while small RNA sequencing was additionally
used to determine the functional role of miRNA in this system. Differential
expression analysis revealed translational fluctuations were most pronounced
immediately after depolarization, wherein gene products involved in synaptic
function were transiently prioritized. Surprisingly, this translational activity
exhibited poor concordance with changes in mRNA abundance, however
these factors progressively became synchronized during the experimental
time-course. Although the most prominent change in miRNA expression
coincided with this early excitatory phase, expression of these molecules was
found to be more inversely proportional to mRNA stability than translation,
with the number of expressed miRNA binding sites determining the
magnitude of mRNA destabilization. Our findings indicate neuronal excitation
generates complex profiles of mRNA translation, which are initially regulated
independently of underlying changes in mRNA abundance or miRNA
expression. We suspect alternative regulatory systems play a role in coordinating
early patterns of excitation-associated translational activity in neuronal cells.

M32. NRAP-1 is a Protein Ligand for the NMDAR Amino-

Terminal Domain
Dayton Goodell*, Jerry Mellem, Ning Lei, David Madsen, Andres Maricq
The NMDA-receptor (NMDAR) subtype of ionotropic glutamate receptors
(iGluRs) has fundamental roles in the processing and encoding of information,
and in humans, defects in NMDAR signaling are a hallmark of many

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neurological disorders. Recently, a genetic screen for modifiers of NMDAR
function in C. elegans identified a presynapticaly secreted protein, NRAP-1,
that is required for the gating of NMDARs. Additionally, NRAP-1 is rate
limiting for NMDAR function, and thus is likely to control the magnitude of
NMDAR signaling. Here we show that NRAP-1 is a NMDAR amino-terminal
ligand with nM affinity sufficient to partially gate open the NMDAR in the
absence of glutamate. Furthermore, we identify the domains of NRAP-1 that
modify NMDAR gating. We also demonstrate that select vertebrate proteins
that contain NRAP-1 domains when modified with simple amino acid
substitution also gate C. elegans NMDARs. Because of the deep evolutionary
conservation of iGluRs and glutamatergic signaling, we anticipate that similar
signaling mechanisms might also contribute to the regulation of vertebrate
NMDAR signaling. Additionally, comparisons of the evolutionary divergence of
NMDAR gating made possible by the results of this study provide fundamental
insights into the design and function of NMDARs allowing for new conceptual
framework for drug discovery that could ultimately motivate novel approaches
for therapeutic intervention in neurological disease characterized by disrupted
NMDAR function.

TUESDAY, JANUARY 28, 2020 • 3:30 P.M. - 4:30 P.M. • JEFFERSON/MADISON

T1. Hierarchical Cue Control of Cocaine Seeking in the

Face of Cost
Anne Collins*, Benjamin Saunders
Drug addiction is characterized by intermittent, persistent drug seeking despite
rising costs. Drug-associated cues are a powerful trigger of this behavior,
capable of inciting relapse in recovering addicts. We set out to model three key
aspects of human drug use in rats: the intermittent, binge-and-stop nature of
drug intake, the motivational conflict of drug seeking in the face of escalating
negative costs, and the ability of different types of drug cues to modulate
seeking and spur relapse. Critically, we found that the ability of proximal cues
to trigger relapse was gated by the presence of a global cue signaling drug-
availability within the animal’s environment, suggesting that hierarchical
cue interactions exert an important modulating influence on drug-seeking
motivation. Dopamine release within the nucleus accumbens core (NAc) has
been implicated in cue-induced relapse of drug seeking. It is less clear, however,
if dopamine signaling may encode hierarchical drug-related learning states
where drug cues interact to guide seeking. To address this, we measured changes
in dopamine receptor activity within the NAc core with fiber photometry, using
the genetically encoded dopamine sensor dLight. Our preliminary data suggests
that the dopaminergic signaling profile in the NAc core changed throughout
binge-like drug use, as rats learned to pattern their intake in response to global

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signals of drug availability. Together these results demonstrate hierarchical cue
control of drug seeking despite cost, and point to a role for NAc core dopamine
in this process.

T2. In Vivo Identification and Modulation of Appetitive

Memory-Related Circuit Elements in the Mouse Prefrontal
Cortex
Roger Grant*, Elizabeth Doncheck, Elizaveta Romanova, James Otis
The prefrontal cortex (PFC) is a hotbed of heterogeneous cell types that
integrate sensory, motivational, and memory-related information to help
guide learned behaviors. However, activity in PFC can become maladaptive
in individuals suffering from substance use disorder (SUD), with that activity
being a reliable predictor of future relapse. Despite the known involvement of
PFC, in particular the prelimbic sub-region of medial PFC (PL-mPFC), how
heterogeneously-responding cortical cell types contribute to reward-seeking
behaviors is not yet fully understood. Here, we use in vivo two-photon calcium
imaging to define multiple excitatory PL-mPFC cell clusters that respond in
unique manners to reward-related cues. In addition, we find that inhibition of
noradrenergic receptors, primary neuromodulator receptors that influence cue-
induced reward seeking, with the pharmacological antagonist propranolol (i.p.,
10 mg/kg) can persistently impair cue-driven sucrose seeking in a Pavlovian
conditioning task. Furthermore, we find that cue encoding in excitatory cell
clusters of the PL-mPFC was also perturbed under these conditions. Our
research suggests that noradrenergic signaling is a primary mechanism that
allows cues to drive reward-seeking behavior under normal conditions, likely
by modifying the cue-encoding properties of excitatory output neurons in
PL-mPFC. Next, we aim to understand how noradrenaline influences cue
encoding and reward-seeking behaviors in a rodent model of drug addiction.

T3. Investigating the Effects of Controllable Stress on

Future Behavioral and Neuronal Responses to Reward- and
Drug-Associated Cues
Kayla Siletti*, Kyle Brown, Michael Saddoris
Even after prolonged periods of abstinence, stress can potently trigger drug
cravings and induce relapse. Uncontrollable stress prior to exposure to drug-
associated cues (e.g. paraphernalia) can generate enhanced vulnerability to
relapse. However, perceived control over a stressor produces vastly different
behavioral outcomes. These stressors, while still aversive, have been shown
to endow animals with resilience against future stressors, even when these
stressors occur in different contexts or require unique actions. In an animal
model of stressor controllability, rats can turn a wheel to escape tail-shock

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(escapable stress; ES). Yoked animals receive physically identical shock but
cannot turn a wheel; thus, they have no such perception of control (inescapable
stress; IS). After a single session of repeated trials, ES-experienced animals
express reduced neophobia and hypervigilance, characteristic of stress-naïve
home-cage controls, whereas their IS counterparts exhibit heightened states of
anxiety.
Animals with a history of chronic cocaine self-administration similarly
demonstrate different behavioral outcomes following controllable and
uncontrollable stressors. These stressors differentially modulate how cocaine-
experienced animals learn about and respond to cues associated with natural
and drug rewards. Here, we demonstrate that electrophysiological responses
in the nucleus accumbens to reward-predictive cues during abstinence are
dampened following exposure to uncontrollable stress, but controllable stress
protects against such deficits in cue responsivity. Ongoing work is examining
how these unique stress experiences may alter drug-associated cue responses,
in ways that accelerate the extinction of drug-seeking behaviors and mitigate
neuronal adaptations taking place over the first 30 days of drug abstinence.
Collectively, these data suggest that control over stressful experiences or lack
thereof may produce opposing effects on reward- and drug-seeking.

T4. Kappa-Opioid Receptor Antagonism Reverses Heroin

Withdrawal-Induced Allodynia
Renata Marchette*, Adriana Gregory-Flores, Brendan Tunstall, Agnieszka Sulima,
Kenner Rice, Leandro Vendruscolo, George Koob
Although opioids are potent analgesics, chronic opioid use leads to allodynia
(defined as pain due to a stimulus that is not normally painful) that is observed
during withdrawal and contribute to opioid addiction. There is evidence
supporting the involvement of kappa opioid receptors (KOR) in allodynia
in chronic pain models. However, the role of KOR in opioid withdrawal-
induced allodynia/hyperalgesia remains to be determined. Because KORs are
upregulated in brain regions in opioid dependent rats, we hypothesize that
KOR antagonist would revert opioid withdrawal-induced allodynia. To test
our hypothesis, we first investigated the selectivity of 5’-guanidinonaltrindole
(GNTI) in antagonizing the analgesic effect of KOR agonism in the tail
flick test. We found that GNTI blocked the analgesia induced by U50,488, a
selective KOR agonist. To investigate the potential of GNTI to reverse opioid
withdrawal-induced allodynia, male and female Wistar rats received daily
injections of heroin (diamorphine hydrochloride, 2-6 mg/kg, s.c.) and were
tested for mechanical sensitivity with an electronic von Frey (eVF) 4-6 h into
heroin withdrawal. Both male and female, heroin-treated rats exhibited reduced
paw withdrawal thresholds compared with the saline group, indicating the
development of allodynia. Females required higher doses of heroin. Next, the

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rats received vehicle (saline, 1 mL/kg), 24 h before eVF testing and on the next
day, GNTI (30 mg/kg, s.c.), testing was repeated 24 h, 96 h, 7 and 14 days after
GNTI treatment. In male and female rats, paw withdrawal thresholds were
significantly higher after GNTI treatment, reversing heroin withdrawal-induced
allodynia in rats of both sexes, an effect that lasted for at least 96 h. These
findings indicate, a functional role of KOR in the allodynia induced by heroin
withdrawal in both sexes.

T5. Intratelencephalic and Pyramidal Tract Neurons

Differentially Mediate Cocaine Sensitization and
Conditioned Taste Aversion
Elizabeth Crummy*, Aaron Garcia, Isah Webb, Reiley Durre, Susan Ferguson
Intratelencephalic (IT) and Pyramidal Tract (PT) are two classes of
glutamatergic cortical projection neurons that exhibit unique morphology,
firing patterns, and connectivity. However, little is known about their functional
role in mediating behavioral outputs. We have recently found distinct roles of
IT and PT neurons in anterior cingulate cortex (ACC) in the appetitive and
aversive components of cocaine use Specifically, inactivation of IT neurons
blunted a cocaine-induced sucrose aversion, whereas PT inactivation increased
the cocaine place preference and transiently altered cocaine sensitization.
Nonetheless, how IT neurons influence additional dimensions of substance
use, including the locomotor sensitization to cocaine, has yet to be elucidated.
To address how IT neurons contribute to sensitization and if IT inactivation
inherently alters aversive processing, IT neurons were chemogenetically
modulated in ACC. Rats were either pretreated with CNO (5 mg/kg, i.p.)
or vehicle (5% Dimethyl sulfoxide in sterile water, i.p.) 30 minutes prior
to treatment with either cocaine (15 mg/kg, i.p.) or saline (0.9%, i.p.) for
seven sessions. Two weeks following the last session, all groups were given a
challenge in cocaine injection (10 mg/kg). To assess the inherent effects of
IT inactivation on aversive responses, rats were given access to a 15% sucrose
solution followed by i.p. injections of CNO or vehicle and subcutaneous
injections of saline. Inactivation of IT neurons in ACC heightened locomotor
activity during early cocaine exposure, in contrast to PT inactivation.
Furthermore, IT inhibition is not in of itself aversive, suggesting that alterations
of a cocaine-induced CTA was not just due to loss of IT activity. Ongoing work
will confirm these findings. Additionally, examining the role of these cell types
in contingent cocaine administration and relapse behaviors will provide greater
understanding of their role in processing motivational facets of substance use.

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T6. Neurobiological Correlates of Low Nicotine and
Cannabis Exposure
Hugh Garavan*
The increased availability of cannabis (legalization and decriminalization) and
nicotine (vaping) has raised concerns that use of these substances will increase
in adolescence, a period during which the developing brain may be especially
susceptible to the effects of substances with abuse potential. Longitudinal
studies of adolescents can help identify potential consequences of substance
exposure. In this poster, I will present data from the IMAGEN study, a ten-
year longitudinal study of 2,000 European adolescents. This study contains
extensive phenotyping, including functional and structural brain imaging, and
genotyping with assessments at ages 14, 16, 19 and 23. The analyses of the
brain data at age 14 show structural differences associated with very light use
(1/2 cigarettes; 1/2 joints). Analysis of the longitudinal data suggest that these
effects did not precede use. Furthermore, a magnified effect (volume reduction
in the vmPFC) in smokers with a high-risk alpha5 nicotinic receptor gene
suggests the smoking effects are mediated, in part, by the nicotinic system. The
widespread subcortical effects associated with light cannabis use are in regions
high in CB1 receptors, adding evidence that this effect may be related to the
cannabinoid system. The implications of these observations for theories of
addiction will be discussed.

T7. Excitation of Nucleus Accumbens D1 Medium Spiny

Neurons and Facilitation of Dopamine Release via
Activation of the Muscarinic M1 Receptor Regulates
Motivated Behavior
Samantha Yohn*, James Maksymetz, Weilun Qian, Ellen Rieth, Zixiu Xiang, Joseph
Cheer, Erin Calipari, Craig Lindsley, Jeff Conn
Motivational symptoms are debilitating features of several neuropsychiatric
disorders and are highly correlated to long-term treatment outcomes. Recent
studies have highlighted the regulatory role of nucleus accumbens (NAc)
dopamine (DA) release and D1 medium spiny neurons (MSNs) in motivated
behavior. Reductions in NAc DA release and augmented excitability of
D1-MSNs have been correlated with anhedonic-like phenotypes, suggesting
that agents that modulate DA release and D1-MSN activity may be efficacious
for motivational dysfunctions. Gq/11-coupled muscarinic acetylcholine
(mACh) M1 receptors are highly expressed in the NAc and have been reported
to regulate the transition states of striatal MSNs and DA transmission. Herein,
we investigate the ability of highly selective M1 compounds to modulate NAc
microcircuitry. We assessed M1 activation on NAc DA release via in vivo fast
scan cyclic voltammetry, examined real-time activity of M1 activation on NAc

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D1-MSNs in vivo by recording calcium (Ca2+) transients in D1-cre mice,
and evaluated motivated behavior through use of an effort-related choice
assay. Excitingly, we found that activation of M1 increased NAc DA release
by 50% compared to baseline conditions and enhanced D1-MSNs Ca2+
transient frequency and amplitude compared to saline-control conditions.
Moreover, pharmacological activation of M1 increased selection of higher
effort alternatives. Together, these experiments may help to elucidate precise
neural circuit dynamics that underlie aberrations in motivated behavior, which
could lead to the development of safe and effective treatments for motivational
dysfunctions.

T8. DG3-80: A Novel Fluorescent DAT Ligand Ideal for

Live Super-Resolution Microscopy
Amy Newman*, Daryl Guthrie, Carmen Herenbrink, Matthew Lycas, Therese Ku,
Alessandro Bonifazi, Luke Lavis, Ulrik Gether
The dopamine transporter (DAT) plays a critical role in regulating dopamine
homeostasis and is the principle target for widely abused psychostimulants,
such as cocaine and methamphetamine. Alteration in dopamine signaling and
DAT function is also associated with neurological and psychiatric disorders
including Attention Deficit Hyperactivity Disorder and Parkinson’s Disease.
Nonetheless, little is known about the cellular distribution and trafficking of
endogenously expressed DAT in these conditions and how they are affected
by drugs of abuse or prescription medications. One approach to begin to
understand mechanisms underlying the molecular and cellular processes
governing the activity and availability of DAT in the presynaptic nerve
terminals is to use fluorescent tools. We have developed high affinity and DAT-
selective fluorescent small molecules that permit the detection and tracking of
DAT, which in turn, allows us to study the plasma membrane surface dynamics
and distribution of DAT in dopaminergic neurons. Previously, JHC1-064,
which like cocaine binds to an outward facing conformation of DAT, has been
used to visualize DAT trafficking. We have recently optimized and validated
a new fluorescent tool, DG3-80, that may be superior for super-resolution
microscopy. This novel DAT ligand links the Janelia Fluor 549 dye to a cocaine-
derived tropane scaffold via a polyethyleneglycol linker and allows the detection
of endogenously expressed DAT in CAD cells and DA neurons using dSTORM.

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T9. Behavioral, Autonomic, and Neural Evidence of Sex
Differences in the Human Reward System
Katherine Warthen*, Alita Boyse-Peacor, Keith Jones, Benjamin Sanford, Tiffany
Love, Brian Mickey
Affective disorders and addictions, along with other psychiatric disorders, affect
men and women differently. Given the extent that the reward system is involved
in these disorders, we hypothesized that reward behavior and physiology
would differ between the sexes. We quantified the sex differences in reward
responses in 221 healthy young adults during a monetary incentive task that
engages the mesoaccumbal pathway and salience network. Stimuli varied by
salience and valence (behavioral relevance vs. positivity and negativity). We
measured reward related traits, task behavior, autonomic activity as reported
by skin conductance, and fMRI neural responses to generate evidence
spanning multiple neurobehavioral levels. Men reported higher levels of
reward sensitivity, fun seeking, and appetitive motivation relative to women.
Men also showed greater subjective arousal ratings, behavioral accuracy, and
skin conductance responses. In imaged subjects (n=44), men showed greater
responses to salience in the nucleus accumbens, midbrain, anterior insula,
and dorsal anterior cingulate cortex. Responses to valence as measured by
behavioral autonomic, and neural sensitivity did not differ between the sexes,
indicating that these differences were present in both win and loss conditions.
We reveal novel and robust sex differences in the processing of salient stimuli.
These outcomes indicate a neurobehavioral basis for sexual dimorphism in
disorders of the reward system.

T10. Excitatory Regulation From the Parabrachial Nucleus

to the Ventral Tegmental Area Mediates Unanticipated
Long-Term Memory of Aversion
Smriti Mongia*, Huiling Wang, Shiliang Zhang, Carlos Mejias-Aponte, Jorge
Miranda-Barrientos, Marisela Morales
The ventral tegmental area (VTA) is a brain structure well known for containing
dopamine neurons that have been implicated in motivation, addiction, decision
making, aversion and pain. While it has been suggested that different types
of VTA dopamine neurons participate in these different behaviors, emerging
findings suggest that some of these behaviors may also be mediated by VTA
non-dopamine neurons. In this regard, we have recently demonstrated that
the VTA has a subset of glutamatergic neurons (expressing vesicular glutamate
transporter 2, VGluT2 mRNA) that are involved in aversion. Here, we
conducted monosynaptic rabies tracing studies to determine the upstream
neurons that may regulate the activity of VTA glutamatergic neurons. From
these tracing studies, we found that the VTA glutamatergic neurons received

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inputs from the parabrachial nucleus (PBN), a brain area implicated in aversive
behavior. Next, we determined the phenotype of PBN neurons innervating
the VTA by using a combination of chemical neuronal tracing and in situ
hybridization and found that the vast majority of PBN neurons that innervate
the VTA expressed VGluT2 mRNA. Given that these findings suggest that
PBN-glutamatergic neurons excite VTA-glutamatergic neurons, we combined
viral tracing techniques with immuno ultrastructural analysis, and found that
axon terminals from PBN neurons (containing VGluT2-protein) established
asymmetric (excitatory type) synapses on VTA VGluT2-positive neurons.
To confirm the excitatory nature of the PBN synapses on VTA-glutamatergic
neurons, we used a combination of viral tract tracing, optogenetics and slice
electrophysiology and found that glutamate released from PBN-glutamatergic
innervations evoked the firing of VTA-glutamatergic neurons. Next, by
combination of optogenetics and behavior analysis, we found that VTA
laser-induced release of glutamate from PBN inputs resulted in place aversion.
Moreover, in the absence of laser-stimulation, this aversion was maintained
for up to 60 days. In summary, we provide compelling evidence indicating that
glutamatergic inputs from the PBN to the VTA are part of a neuronal network
that mediates long-lasting memory of aversive signaling.

T11. Genetic Dissection Reveals Different Roles for

Intrinsic and Extrinsic Catecholaminergic Innervation of
the Cognitive Cerebellum
Erik Carlson*, Avery Hunker, Stefan Sandberg, Shelby Johanson, Timothy Locke,
Paul Phillips, Larry Zweifel
We have previously shown that the dopamine D1 receptor marks a population
of neurons in the LCN regulates cognitive performance on several tasks related
to attention and working memory and has connections with other parts of
the brain that are classically involved in these functions. We hypothesized
that the locus ceruleus (LC) is the source of norepinephrine release in LCN,
that Purkinje cells (PCs) expressing tyrosine hydroxylase (Th) are the source
of dopamine release in LCN. We have mapped LC projections to LCN, and
analysis revealed distinct projections from the locus ceruleus, but no other
nuclei outside of the cerebellum known to produce catecholamines. When
we injected DBH-IRES-Cre; TdTomato mice with green retrobeads in LCN,
we found overlap of the retrobeads and tomato staining, suggestive of LC
projections to LCN. LC stimulation results in catecholamine release in the
LCN is observed with cyclic voltammetry. We also mapped the expression
of Th in a subset of PCs in the cerebellum. Deletion of Th in LCN results in
abnormal performance on working memory, response inhibition, and sensory
discrimination behaviors. Th lox/lox mice were injected with CAV-Cre
(retrograde virus) into LCN and trained on either an impulsivity or a delayed

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alternation task. Littermate controls were injected with CAV2 encoding the
fluorophore, zsGreen. Tyrosine hydroxylase was reduced by 75% in the LCN
verified by Western blot. LCN TH knockout mice showed more impulsive
pressing than littermate controls. LCN TH knockout mice showed impairment
in learning delayed alternation. Furthermore, we used two approaches to
target Th expression in either PCs or the LC->LCN projection. First, we
selectively knocked out Th in PCs by crossing a Pcp2-Cre line with Th lox/
lox mice, in which the LCN Th expression is reduced by 50%. Second, we
used a combinatorial viral approach to specifically knock out Th expression in
the LC->LCN projection by injecting Cav-Cre in the LCN and a CRISPR Th
knockout construct (AAV1-FLEX-SaCas9-U6-sgTh) into the LC. We then
examined a selection of behaviors and found differing effects in Pcp2-Cre;Th
lox/lox mice and mice injected with both LC: AAV1-FLEX-SaCas9-U6-sgTh
and LCN: Cav-Cre, suggesting different roles for each of these sources of
catecholamines in the LCN.

T12. VTA Glutamate Neurons Promote Aversion by

Activation of mPFC Parvalbumin Neurons
Huiling Wang*, Huikun Wang, Flavia Barbano, Marisela Morales
Dopamine inputs from the ventral tegmental area (VTA) to the medial
prefrontal cortex (mPFC) have been implicated in neuropsychiatric pathologies
for decades. Recent findings indicate that the mPFC is also innervated by
VTA neurons expressing the vesicular glutamate type 2 (VGluT2). However,
it is unclear the extent to which the subdivisions of the mPFC are targeted by
the different subclasses of VTA VGluT2 neurons. In this study, we injected
the retrograde track tracer fluorogold (FG) in either the prelimbic (PrL) or
infralimbic (IL) cortex of wild type rats, and phenotyped the VTA FG-positive
(mesocortical) neurons by a combination of in situ hybridization (to
detect VGluT2 mRNA or glutamate acid decarboxylase, GAD mRNA) and
immunohistochemistry (to detect both FG and tyrosine hydroxylase [TH]).
For the mouse analysis of mesocortical VGluT2 neurons, we injected the
AAV-DIO-eYFP viral vector into the VTA of VGluT2::Cre transgenic mice. In
these mice, we also injected FG into the PrL or IL cortex, and evaluated VTA
co-expression of FG and eYFP neurons. In rats and mice, we found that (1)
both IL and PrL cortex received inputs from VTA neurons, but these VTA
neurons provided 4.4 times more inputs to the IL than PrL cortex. (2) Four
classes of VTA neurons innervated the mPFC: TH-only, VGluT2-only, dual
VGluT2-TH, and GABA-only. (3) The VTA inputs to mPFC were mostly from
VGluT2-only, TH-only and dual VGlu2-TH neurons, and less frequently from
dual VGluT2-GABA or GABA-only neurons. By photoactivation of mPFC
VGluT2 inputs from VTA neurons, we found that this mesocortical VGluT2
pathway induced conditioned place aversion, which depended on activation
of both glutamate and GABA receptors. Next, we determined the type of IL

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neurons activated by the mesocortical VGluT2 pathway and found that this
pathway induced c-Fos expression in parvalbumin (PV) GABA interneurons.
By electrophysiological and ultrastructural analysis, we found that PV neurons
of the IL cortex were the major target of VTA VGluT2 terminals (Dr. Zhang’s
abstract). Our findings indicate that the VTA provides a glutamatergic
excitatory input to a subpopulation of IL cortical PV-GABAergic neurons, and
that activation of these PV neurons inhibits neighboring pyramidal neurons,
promoting aversive behavior.

T13. Characterization of the Affective State and Neural

Correlates During Empathic Behavior in Rats
Stewart Cox*, Brogan Brown, Angela Kearns, Carmela Reichel
Prosocial behaviors, such as social interaction and empathy, are imperative
for an adaptive social structure by the allowance for personal understanding
of the perceived valence of others. Further, these behaviors may play a role in
the underlying pathology of numerous cognitive disorders. Research suggests
animals will behave prosocially in the hopes of receiving social reward, but
only recently has it been intimated some animals are capable of behaving
empathically. Empathy is defined as the capacity for one to experience the
valence of another, thereby generating a response more appropriate to another’s
emotional situation than one’s own, independent of personal gain. We have
developed a model of empathic behavior that requires the animal to pull a
chain to release a distressed conspecific from 100mm of water via an automated
guillotine door. Importantly, we designed the apparatus to eliminate the
social reward as a motivator for the observed behavior. We have characterized
this model to ensure specificity of the release behavior through a series of
experiments varying the level of distress to the conspecific. Here we extend
our previous work to female rats. We initially hypothesized that female rats
would show greater empathic processes relative to males, but both learn to
release a conspecific at the same rate. During the task we collected ultrasonic
vocalizations (USVs) to begin to identify the rats’ affective state and data are
being analyzed with the detection software DeepSqueak. To date, we have
identified several different categories of USV calls based on call Hz with the
range of prosocial and distress calls. Future, experiments will evaluate the role of
several neural substrates, including the insular cortex and basolateral amygdala,
during the task. Our lab’s model allows for an evaluation of empathic behavior
in rats, as well as an elucidation of the neural underpinnings of empathy and
how they are affected by cognitive disorders like SUD.

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T14. The Dynamics of Brain Connectivity at Rest
Underpins Performance in Task
Yvonne Yau*, Filip Morys, Alain Dagher
Flexible human cognition depends on the ability of brain circuitry to transiently
express various functional configurations, coined intrinsic connectivity
networks (ICNs). Time-varying functional connectivity (tvFC) quantitatively
characterizes reoccurring brain patterns (i.e., “states”) and their dynamic
functional properties. These metrics allow us to observe the dynamic interplay
within and between ICNs at the time scale that cognitive processes operate at.
Here, we employed a data-driven approach to assess tvFC based on established
techniques including: whole-brain independent component analysis to identify
ICNs and k-mean clustering of fixed-length sliding windowed correlation
matrices to identify brain states. 4 connectivity states were identified from
our resting state fMRI data and were tested against behavioral performance
in a perceptual decision-making task undertaken in the scanner beforehand
(N=55). Participant’s accuracy in task were related to a greater number
of transitions between states (r=.346, p=.013) and to dwell time in an
anticorrelated state (r=.495, p=<.001) which exhibited high modularity within
the default mode network and negative connectivity to motor-visual systems.
Moreover, the more similar the brain connectivity pattern in task was to the
anticorrelated state at rest, the better their accuracy performance (r=.4077,
p=.003). In a post-hoc analysis, we found participants with longer dwell time
in the anticorrelated state at rest demonstrated greater caudate signal in task
during the deliberation phase. Caudate activity may represent a dopaminergic
stopping signal to slow the deliberation process and promote greater accuracy.
Taken together, these findings suggest that better task performance may be
associated with higher flexibility in network reconfiguration and the propensity
to stay in more optimal brain configurations both at rest and in task. Time-
varying approaches to network neuroscience could reveal insights into the
neural configurations that underpin individual differences in human cognition.

T15. The Effect of Subthalamic Nucleus Deep Brain

Stimulation on Effort Discounting
Guillaume Pagnier*, Wael Asaad, Michael Frank
Parkinson’s disease (PD) is a common neurodegenerative disease affecting
1% of the elderly population. High frequency deep brain stimulation (DBS)
in the subthalamic nucleus (STN) improves motor symptoms, but its precise
mechanism of action is still unclear. In cognitive tasks, DBS can lower the
‘decision threshold’ and increase impulsivity by disrupting the STN theta-band
modulation in response to cognitive conflict. These results contrast with the
effects of dopaminergic medication (which alter the weighting of benefits vs

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costs of decisions), and have been interpreted in terms of an informational
lesion induced by DBS. Here we evaluate whether low vs high frequency
stimulation in different STN contact locations (dorsal vs ventral) can have
differential effects on decision threshold or cost-benefit decision making in a
physical effort-discounting task. We present behavioral data and spontaneous
eye blink rate data to clarify STN DBS’ effects on cost/benefit decision making.

T16. Mechanisms of Prefrontal Circuit Assembly

Cassandra Klune, Benita Jin*, Christopher Gabriel, Rakasa Pattanaik, Vincent Xu,
Laura DeNardo
Critical functions including memory guided behaviors, decision making, and
social behaviors are all dependent on the medial prefrontal cortex (mPFC).
mPFC is interconnected with a distinctly large set of brain regions, each
with unique behavioral functions. Neurons in mPFC undergo a protracted
period of development which likely explains why its circuitry is implicated in
numerous neuropsychiatric disorders. Despite the crucial function and unique
vulnerability of mPFC circuitry, the mechanisms underlying the assembly of
these circuits are not known. Using viral approaches to label mPFC projection
neurons in the postnatal brain, we are mapping the developmental time course
of mPFC synapse formation in select target regions including the nucleus
accumbens and basolateral amygdala. In conjunction within situ hybridization
to label transcripts for synaptic adhesion proteins, we are also identifying genes
poised to specifically wire distinct aspects of mPFC circuitry. Using these genes
as footholds, we will then manipulate mPFC circuit assembly to link key events
in the maturation of specific mPFC connections to the emergence of adaptive
behaviors over development. These experiments will provide insights into
the molecular specificity within mPFC projection neurons that allow them to
properly assemble, and how their assembly contributes to the maturation of
complex behaviors.

T17. Diet Modulates Brain Network Stability, a Biomarker

for Brain Aging, in Young Adults
Lilianne Mujica-Parodi*, Anar Amgalan, Syed Sultan, Botond Antal, Xiaofei
Sun, Steven Skiena, Andrew Lithen, Eva Maria Ratai, Corey Weistuch, Sindhuja
Govindarajan, Helmut Strey, Ken Dill, Steven Stufflebeam, Richard Veech, Kieran
Clarke
Epidemiological studies suggest that insulin resistance accelerates progression
of age-based cognitive impairment, which neuroimaging has linked to brain
glucose hypometabolism. As cellular inputs, ketones produce 27% more ATP
per unit oxygen than glucose. Here we test whether dietary changes are capable
of modulating sustained functional communication between brain regions

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(network stability), by changing their predominant dietary fuel from glucose
to ketones, thereby increasing neuron-accessible ATP. We first established
network stability as a biomarker for brain aging using two large-scale (N=292,
ages 20-85 years; N=636; ages 18-88 years) 3T fMRI datasets. To determine
whether diet can influence brain network stability, we additionally scanned
42 adults, ages <50 years, using ultra-high-field (7T) ultra-fast (800ms) fMRI
optimized for single-participant-level detection sensitivity. One sample was
scanned under standard diet, overnight fasting, and ketogenic diet conditions.
To isolate the impact of fuel type, an independent overnight fasted sample
was scanned before and after administration of a calorie-matched glucose and
exogenous ketone ester (D-β-hydroxybutyrate) bolus. Across the lifespan,
brain network destabilization correlated with decreased cerebral metabolic
activity and cognitive acuity. Effects emerged at 47•4 years, with the most rapid
degeneration occurring at 60•08 years. Networks were destabilized by glucose
and stabilized by ketones, irrespective of whether ketosis was achieved with
a ketogenic diet or exogenous ketone ester. Together, our results suggest that
brain network destabilization may reflect early signs of hypometabolism, a
biomarker for brain aging. Dietary interventions that result in ketone utilization
increase neurometabolic efficiency, and thus may show potential in protecting
the aging brain.

T18. VR Brain Exploration: Explore and Manipulate a 3D

Brain to Alter CNS Mechanisms of Satiety and Hunger
Bradley Tanner*
Neuroscience is quickly unraveling the neurochemistry and neurobiology
behind obesity in increasingly fine detail. The model of the brain’s impact
on eating behavior is advancing rapidly. That model is expanding our
understanding of mechanisms that regulate not only satiety and hunger but
processes and structures that impact thermogenesis, basal metabolic rate, and
activity. Unfortunately, the tools to explain this complicated system have not
evolved as rapidly. We have been limited to charts, videos, and diagrams that are
inadequate for most everyone except neuroscientists. With 3D models and the
Oculus Quest, the capability of these tools now matches the complex world of
the brain.
Learners in a variety of stages of life and disciplines can benefit from an
exploration of the brain that allows direct exposure to and manipulation of
key brain elements, neurotransmitters, receptors, and pathways. The potential
value of a VR brain exploration can be realized by 1) researchers trying to
explain their findings to other researchers, 2) clinicians trying to understand the
mechanisms and impact of current and future drugs as well as chemicals such
as cannabis, 3) patients attempting to understand why they are struggling with

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the problem as well as the potential impact of interventions, and 4) the general
public curious about a system that they deal with multiple times a day every day
of their life, yet is mysterious.
A poster can discuss the power of the technology but to understand the
potential of headset VR one must explore the VR brain in a truly immersive
VR headset. The Oculus Quest is the first VR Headset with sufficient power
and capability to deliver such an experience without wires or the need for
a computer. The poster will thus include the opportunity to experience the
potential of the technology to confer a 3D experience. In that experience, one
is immersed in the complexity and beauty of a functional model of the brain
emphasizing obesity-related structures and activity.

T19. Neuronal Protein Tyrosine Phosphatase 1B Drives the

Progression of Amyloid β-Associated Alzheimer’s Disease
Alex Stewart*, Konrad Ricke, Shelly Cruz, Zhaohong Qin, Kaveh Farrokhi, Michael
Zasloff, Hsiao-Huei Chen
Alzheimer’s disease (AD) is the most common neurodegenerative disorder,
resulting in the progressive decline of cognitive function in patients. Familial
forms of Alzheimer’s Disease (AD) are tied to mutations in the amyloid
precursor protein, but the cellular mechanisms that cause AD remain unclear.
Neuroinflammation and amyloidosis from amyloid beta (Aβ) aggregates
are implicated in neuron loss and cognitive decline. Since inflammation
activates the protein-tyrosine phosphatase 1B (PTP1B), this could suppress
many signaling pathways that activate glycogen synthase kinase 3β (GSK3β)
implicated in neurodegeneration. Here, we show that either neuronal ablation
or selective inhibition of PTP1B in a transgenic AD mouse model with Aβ
pathology (hAPP-J20 mice) delays the decline of spatial memory and prevents
hippocampal neuron loss, likely in part by restoring inhibition of GSK3β.
Intriguingly, while systemic inhibition of PTP1B reduced neuroinflammation,
neuronal PTP1B ablation did not, suggesting that inflammation is not sufficient
to cause neuron loss and cognitive deficits without neuronal PTP1B. In
addition, ablation of PTP1B reduced hippocampal Aβ plaque size, without
altering Aβ protein concentration or plaque load. Our results demonstrate
that neuronal PTP1B may drive AD-associated neurodegeneration and loss of
memory. In addition, we present a new strategy to intervene in the progression
of AD.

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T20. Pomalidomide Analogues to Mitigate
Neuroinflammation in Neurodegenerative Disorders –
From Traumatic Brain Injury to Alzheimer’s Disease
Nigel Greig*, Daniela Lecca, Yoo Jin Jung, David Tweedie, Michael Scerba, Weiming
Luo, Dong Seok Kim, Barry Hoffer, Chih-Tung Lin, Ling-Yu Yang, Jia-Yi Wang
Traumatic brain injury (TBI) causes mortality and disability worldwide
and, additionally, is a risk factor for chronic neurodegenerative conditions
exemplified by Alzheimer’s and Parkinson’s disease. TBI can instigate acute
cell death followed by secondary injury induced by microglial activation,
inflammation, oxidative stress and autophagy in brain tissue, resulting in
cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom)
analog, 3,6’-dithioPom (DP), and Pom as immunomodulatory agents to
mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral
impairments in rats challenged with controlled cortical impact TBI. Both
agents significantly reduced the injury contusion volume and degenerating
neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with
a therapeutic window of 5 hr post injury. TBI-induced upregulated markers
of microglial activation, astrogliosis and the expression of proinflammatory
cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed;
leading to an amelioration of behavioral deficits with DP providing greater
potency. Complementary animal and cellular studies demonstrated DP and
Pom mediated reductions in markers of neuroinflammation and of both
amyloid-beta- and alpha-synuclein-induced toxicity. DP is a novel and potent
Immunomodulatory Drug (IMiD) that warrants further development as a
new treatment option for acute and chronic neurodegenerative disorders
characterized by a neuroinflammatory element.

T21. ITPKB, a Parkinson’s Disease GWAS hit, Modulates

A-Synuclein Pathophysiology in Cellular Models
Daniel Apicco, Ed Guilmette, Evgeny Shlevkov, Justin Nicholatos, Catherine Nezich,
G. Campbell Kaynor, Ellen Tsai, KD Nguyen, YuTing Liu, Andreas Weihofen,
Jessica Hurt, Michelle Penny, Warren Hirst*
Inositol-1,4,5-triphosphate kinase B (ITPKB) is one of three protein kinases
in the central nervous system that inactivates inositol-1,4,5-triphosphate
(IP3), a second messenger that modulates intracellular calcium release from
the endoplasmic reticulum (ER). Genome-wide association studies (GWAS)
have identified common variants in the ITPKB locus that are associated with
reduced Parkinson’s disease (PD) risk (odds ratio = 0.92). Here, we investigate
the effect of ITPKB modulation in cellular models of sporadic PD. Knockdown
of endogenous ITPKB using shRNA, or treatment with the pan-ITPK inhibitor
GNF362, increased intracellular calcium levels in mouse primary cortical
neuron cultures, which led to the accumulation of calcium in mitochondria.

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The increase in mitochondrial calcium following ITPKB inhibition was
associated with enhanced mitochondrial respiration, increased ATP production,
accumulation of reactive oxygen species, and activation of caspases. Further,
the effect of ITPKB inhibition on mitochondrial respiration was prevented
by pre-treatment with pharmacological inhibitors of the IP3 receptor or
mitochondrial calcium uniporter, suggesting that ITPKB acts by negatively
regulating the transfer of calcium from the ER into the inner mitochondrial
matrix. Importantly, ITPKB knockdown in mouse cortical neurons resulted
in increased levels of phosphorylated (Ser129) and insoluble α-synuclein
following treatment with α-synuclein preformed fibrils (PFFs). Conversely,
overexpression of human ITPKB reduced α-synuclein aggregation induced
by PFFs. Taken together, these results implicate ITPKB as a critical mediator
of intracellular calcium homeostasis that functions to inhibit α-synculein
pathophysiology in PD. Enhancement of ITPKB kinase activity or expression
may represent a novel therapeutic strategy for the treatment of sporadic PD.

T22. Characterization of Neural Progenitor/Stem Cell

Monolayer and Neurosphere Cultures From Adult Brain
Tissue
Raeden Gray*, Scarlyn De Los Santos, Elizabeth Batsel, Martin Oudega, Jeffery
Plunkett
Adult zebrafish (Danio rerio) have been shown to retain multiple proliferative
neurogenic and stem cell niches to enable growth and repair of central
nervous system (CNS) tissues. We initially developed monolayer cellular
culture conditions that allowed for the in vitro growth of isolated adult brain
cells that contained abundant stem populations. These cultures revealed,
at 7 days in vitro (div), the presence of distinct populations of stem cell-
derived neural progenitor cells that can differentiate into mature neurons and
extend axonal processes. From this data derived in our in vitro monolayer
culture, we have more recently developed a free-floating, rotating aggregate
culture from adult zebrafish brain. After rotating 5 div, these cultures develop
neurospheres of approximately 100-200 micrometers in size and express the
stem progenitor and neural progenitor markers Sox2 and NeuroD1. We are
currently using a combination of immunocytochemical and statistical analyses
to further characterize our neurospheres with an eventual experimental goal of
transplantation into the adult brain following CNS trauma.

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T23. Analysis of Putative Stem and Neural Progenitor Cell
Populations Following Traumatic Brain Injury in Adult
Zebrafish
Melanie Rojas Hammani*, Taylor Schanel, Martin Oudega, Jeffery Plunkett
Although post-embryonic neurogenesis is limited in the mammalian brain,
zebrafish (Danio rerio) retain multiple proliferative neurogenic and stem cell
niches throughout adult life. The focus of our research is to study how traumatic
brain injury (TBI) affects the induction of neurogenic progenitor cell fates in
the adult zebrafish brain. We hypothesize that TBI will induce an endogenous,
quiescent population of progenitor cells that act to integrate and enable the
regenerative response seen following injury in the fish. Our data demonstrate
prior to injury, the putative stem and neural progenitor markers Sox2, neuroD1
and nestin were expressed around and near ventricular areas of ventral
brainstem regions. Furthermore, following 1,3 and 5 days post-TBI, (focal
brainstem injury), unilateral migration of stem cells moving out of ventricular
areas toward the injury epicenter was observed. These migrating cells displayed
an increase in Sox-2, NeuroD1 and PCNA immunoreactivity. We are currently
examining these and other time points with the hope to correlate neural-specific
gene expression with the migration and differentiation of stem progenitor cells
within the injury site.

T24. Functional Magnetic Resonance Imaging as an

Objective Evaluation of Patients With Cerebral Palsy After
Stem Cell Therapy
David Martinez Garza*, Alejandra Garza Bedolla, Ileana Velasco Ruiz, Antonio
Valencia Alcocer, Guillermo Elizondo Riojas, Mariana Mercado Flores, Consuelo
Mancias Guerra, Olga Graciela Cantu Rodriguez, Cesar Homero Gutierrez Aguirre
Stem cell-based therapy (SCT) is an alternative for diseases that, until
recently, were considered intractable, such as cerebral palsy (CP). Efficacy
of SCT has been proven subjectively only through the clinical improvement
of the motor and behavioral symptoms of patients with CP. Functional
magnetic resonance imaging (fMRI) may be used as a tool that can measure
objectively morphological changes that occur in the brain of patient with these
interventions.
We present three pediatric patients with severe neurological deficit as
consequence of hypoxic-ischemic encephalopathy. They received intrathecal
autologous bone marrow (BM) derived total nucleated cells after BM
stimulation with granulocyte-colony-stimulating factor, demonstrating
improvement of their neuropsychiatric functions. A basal fMRI was obtained
and compared with a second fMRI at least 6 months after treatment (figure
1), demonstrating increases on the fractional anisotropy (FA), which

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reflects axonal density and myelination in white matter fibers (table 1),
which correlated with their clinical improvement. Namely, we measured
bihemispheric increases in the corona radiata, the posterior limb of the internal
capsule, and the cerebral peduncles.
It has been demonstrated that stem cells are capable of enhancing neurogenesis
and angiogenesis in affected hypoxic-ischemic brain tissue. Functional MRI
is becoming a powerful tool to evaluate objectively changes occurring in the
central nervous system, specifically in the white matter tracts. Randomized
studies with control subjects are needed to support this possibility.

T25. Expand Your Mind: Evidence for Psychedelic

Enhanced Brain Stimulation
Lucas Dwiel*, Alan Green, Wilder Doucette
Serotonergic psychedelics have recently enjoyed a resurgence in neuroscience
and psychiatry with promising success in psychedelic-assisted therapy for the
treatment of anxiety, depression, and addiction. The mechanism of action
behind this therapeutic effect relies, at least in part, on 5-HT2 agonism which
can be negated with the 5-HT2 antagonist, ketanserin. At the cellular level,
psychedelics have been shown to increase neuritogenesis, spinogenesis, and
synaptogenesis (observed 24 hours after acute administration), effectively
priming neural circuits for neuroplasticity, which may help explain the sustained
efficacy of psychedelic-assisted therapy. To characterize the therapeutic
mechanisms of psychedelics at a neural systems level, the acute drug effects
have been described with functional imaging and neural oscillations. Briefly,
psychedelics increase the entropy of spontaneous cortical activity, thus
relaxing the weight of high-level priors (e.g., beliefs) and allowing for increased
bottom-up information flow. However, it appears that the strongest and most
reliable therapeutic effects of psychedelics manifest when the drugs are paired
with a targeted intervention (e.g., psychotherapy). To better understand
this synergistic interaction without human bias, we investigated the effects
of LSD alone and paired with deep brain stimulation on neural oscillations
in Sprague-Dawley rats. To quantify the difference between brain states we
used the accuracy of predictions from models built with the machine learning
algorithm Lasso. First, we confirmed prior work showing that acute LSD
administration leads to a dramatic shift in neural oscillations compared to
controls (AUC = 0.96 vs. 0.83) which disappear within 24 hours, in agreement
with the pharmacokoinetics of LSD. Second, although rats given LSD 24
hours previously could not be differentiated from control rats, their brains
reacted very differently to deep brain stimulation than controls, suggesting a
synergistic effect between psychedelics and a focal intervention that extends
beyond the immediate effects of the psychedelic. These results demonstrate that

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psychedelics can sensitize, or prime, the brain to future intervention for up to
24 hours – allowing neural activity to be manipulated beyond what is typically
possible.

T26. Periaqueductal Gray and Nociceptive Stimulation

Activates Ventral Tegmental Area Glutamate Neurons
Leah Pappalardo*, Hannah Morgan, Jamie Vizelman, Carlos Mejias-Aponte,
Marisela Morales
The Periaqueductal Gray (PAG) is part of the pain pathway and contains
neurons involved in pronociceptive and antinociceptive functions. The PAG
sends projections to the Ventral Tegmental Area (VTA), an integral part of
the reward pathway. It was recently shown that inactivation of the connection
from the PAG to VTA reduces headache-induced conditioned place aversion,
suggesting that this projection may encode a component of nociception.
Additionally, inactivation of PAG blocks fear conditioning. Our lab has
previously shown that VTA glutamate neurons that project to the lateral
habenula or to the nucleus accumbens produce conditioned place preference
aversion. Therefore, it is possible that the PAG modulation of VTA glutamate
neurons may contribute to the perception of pain. To test this hypothesis,
we injected Cre-dependent GCaMP6f into the VTA of vGluT2-IRES-Cre
transgenic mice and recorded VTA glutamate neuron population responses
during stimulation of the PAG and during pain stimulation of the foot pad. We
found that the VTA glutamate neurons were excited in response to both stimuli.
We are currently confirming these findings by single cell in vivo recordings. This
work was funding by the NIDA Intramural Program.

T27. MEF2C Hypofunction in Neuronal and

Neuroimmune Populations Produces MEF2C
Haploinsufficiency Syndrome Behaviors in Mice
Adam Harrington*, Catherine Bridges, Kayla Blankenship, Ahlem Assali, Stefano
Berto, Benjamin Siemsen, Hannah Moore, Jennifer Cho, Evgeny Tsvetkov, Acadia
Thielking, Genevieve Konopka, David Everman, Michael Scofield, Steven Skinner,
Christopher Cowan
Microdeletions of the MEF2C gene are linked to a syndromic form of autism
termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show
that MCHS-associated missense mutations cluster in the conserved DNA
binding domain and disrupt MEF2C DNA binding. DNA binding-deficient
global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like
behaviors, including autism-related behaviors, as well as multiple deficits in
cortical excitatory synaptic transmission. As a synapse regulator, MEF2C
hypofunction in neurons is presumed to underlie MCHS symptoms, but

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MEF2C is also expressed in microglia. We find that numerous cortical genes
are dysregulated in Mef2c-Hets, including enrichments of autism risk genes,
excitatory neuron genes and microglial genes. Interestingly, conditional Mef2c
heterozygosity in forebrain excitatory neurons reproduces a subset of the
Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia
reproduces social deficits and repetitive behavior. Together our findings reveal
that MEF2C regulates brain development and function through roles in both
neuronal and neuroimmune populations.

T28. Risk of Psychosis in Amphetamine and

Methylphenidate Treated Youth: Role of Gender
Matej Markota*, Rana Elmaghraby, Paul E. Croarkin, William V. Bobo
Introduction: There is increasing evidence that youth with attention deficit
hyperactivity disorder (ADHD) who are treated with amphetamines are
at an increased risk of developing psychosis compared to methylphenidate
treated youth. However, only a fraction of youth treated with amphetamines
develop psychosis. It is currently unclear if an identifiable subgroup of youth
exists that is particularly vulnerable to developing psychosis associated with
amphetamine medications. The goal of this study was to test the hypothesis that
males are more vulnerable to developing amphetamine medication associated
psychosis compared to females. Methods: This was a retrospective, secondary,
analysis of a previously developed population-based cohort of Olmsted
County (Minnesota, U.S.) residents. All cohort members who were diagnosed
with ADHD by 18 years of age and were either treated with amphetamines
or methylphenidates, but not both, were included in the final cohort. Cox
regression models were used to examine the relationships between treatment
and developing any persistent psychotic disorder. Results: Of the 298 youth
included in this study (65.4 % male), a total of 18 (6.0%) were diagnosed with
a persistent psychotic disorder within 12 years of receiving the first stimulant
prescription. Males treated with amphetamines were at a significantly higher
risk of developing psychosis compared to methylphenidate treated peers (HR
7.9, 95% CI 1.7-37.2). There was no significant difference in risk of developing
psychosis between amphetamine and methylphenidate treated females (HR
0.3, 95% CI 0.03-2.2). Conclusion: Our results replicate the findings of a recent
study showing increased risk of developing psychosis in youth treated with
amphetamines compared to methylphenidate treated youth. In addition, our
study suggests that males may be at a higher risk of amphetamine associated
psychosis compared to females.

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T29. Time-Delimited Signaling of MET Receptor Tyrosine
Kinase Regulates Cortical Circuit Development and
Critical Period Plasticity
Shenfeng Qiu*, Xiaokuang Ma
Normal development of cortical circuits, including experience-dependent
cortical maturation and plasticity, requires precise temporal regulation of gene
expression and molecular signaling. Such regulation, and the concomitant
impact on plasticity and critical periods, is hypothesized to be disrupted in
neurodevelopmental disorders. A protein that may serve such a function is
the MET receptor tyrosine kinase, which is tightly regulated developmentally
in rodents and primates, and exhibits reduced cortical expression in autism
spectrum disorder and Rett Syndrome. We found that peak of MET
expression in developing mouse cortex coincides with the heightened period
of synaptogenesis, but is precipitously down-regulated prior to extensive
synapse pruning and peak period of cortical plasticity. These results reflect
a potential on-off regulatory synaptic mechanism for specific glutamatergic
cortical circuits in which MET is enriched. In order to address the functional
significance of the ‘off ’ component of the proposed mechanism, we created
a controllable transgenic mouse line that sustains MET signaling. Continued
MET expression in cortical excitatory neurons disrupted synaptic protein
profiles, altered neuronal morphology, and impaired visual cortex circuit
maturation and connectivity. Remarkably, sustained MET signaling eliminates
monocular deprivation-induced ocular dominance plasticity during the normal
cortical critical period; while ablating MET signaling leads to early closure of
critical period plasticity. The results demonstrate a novel mechanism in which
temporal regulation of a pleiotropic signaling protein underlies cortical circuit
maturation and timing of cortical critical period, features that may be disrupted
in neurodevelopmental disorders.

T30. A Structural Basis for How Ligand Binding Site

Alterations Can Allosterically Regulate GPCR Signaling
and Engender Functional Selectivity
David Sibley*, Marta Sanchez-Soto, Ravi Kumar Verma, Amy Moritz, Comfort
Boateng, Hideaki Yano, R. Benjamin Free, Lei Shi
Signaling bias is the propensity for some agonists to preferentially stimulate G
protein-coupled receptor (GPCR) signaling through one intracellular pathway
versus another. While GPCR agonists have been described that selectively
activate G proteins or β-arrestins, the molecular mechanisms underlying this
biased signaling are not well understood. We recently identified a G protein-
biased agonist of the D2 dopamine receptor (D2R) that exhibits impaired
β-arrestin recruitment. This signaling bias was predicted to arise from unique

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interactions of the ligand with a hydrophobic pocket at the interface of the
second extracellular loop and fifth transmembrane segment of the D2R. Here,
we show that residue F189 within this pocket (position 5.38 using Ballesteros-
Weinstein numbering) functions as a micro-switch for regulating receptor
interactions with β-arrestin. As this residue is relatively conserved among
class A GPCRs, we constructed analogous mutations within other GPCRs
and found that these alterations similarly impaired β-arrestin recruitment
while maintaining G protein signaling. To investigate the mechanism of this
signaling bias, we used an active state structure of the β2-adrenergic receptor
(β2R), to build β2R-WT and β2R-Y199A models in complex with the full
β2R agonist BI-167107 for molecular dynamics simulations. These analyses
identified conformational rearrangements in β2R-Y199A that propagate from
the extracellular ligand binding site to the intracellular surface, resulting in a
modified orientation of the second intracellular loop in β2R-Y199A, which
is predicted to affect its interactions with β-arrestin. Our findings provide a
structural basis for how ligand binding site alterations can allosterically affect
GPCR-transducer interactions resulting in biased signaling.

T31. The Effects of NMDA Receptor Partial Agonism on

rTMS Motor Plasticity
Joshua Brown*, William Devries, Mark George
Transcranial Magnetic Stimulation (TMS) has transformed the approach
to neuropsychiatric illness although many limitations remain. Without a
mechanistic understanding of how TMS produces lasting therapeutic changes
in the brain, advances will be serendipitous and TMS will only reach a fraction
of its potential. There are unlimited combinations of parameters possible in
TMS including stimulation intensity, frequency, pulse width, time on and off,
patterns, and anatomic location. Moreover, the way each of these parameters
affect the brain will change based on brain location, regional cell types, circuits
and activity patterns specific to each disorder, and brain state will all determine
outcome. It is therefore essential to establish the basic mechanism of TMS
effects, so that the explosion of clinically-orientated, hypothesis-driven research
may be guided by a mechanistic rationale.
A few early studies suggested TMS may work through synaptic plasticity
mechanisms including LTP and LTD. Both of these mechanisms depend
on neuronal and NMDA receptor activity. The necessity of this activity has
been supported in several mechanistic studies combining pharmacology with
patterned (Theta-Burst Stimulation (TBS)) or paired (Paired-associative
simulation (PAS), Ischemic Nerve Block (INB)) TMS protocols in humans.
However, the conventional form of TMS used over the last decade for
treatment-resistant depression, 10 Hz repetitive (r)TMS, has never been tested
with pharmacology.

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Here, we report the results of a randomized, double-blind, crossover study
investigating the sufficiency of NMDA receptor activity by administering
d-cycloserine, an NMDA receptor partial agonist, or placebo in 10 Hz rTMS
in ten healthy human subjects. We measured plasticity in the motor cortex
with motor evoked potentials (MEPs) from electromyography (EMG) before
and after rTMS using neurophysiology techniques including: paired pulse
methods to isolate intracortical inhibition and intracortical facilitation; singled
pulse methods assessing the cortical silent period and recruitment curve, and
MEPs over 60 minutes to follow decay over time. The results of this study will
help address the critical gap in mechanistic TMS knowledge, and may provide
insight into the potential for pharmacologic augmentation of TMS.

T32. Overexpression of the Neural Chaperone ProSAAS

Attenuates the Transsynaptic Spread of Synuclein and
Improves Parkinson’s Symptoms in Rodent Models of PD
Iris Lindberg*, Michael Helwig, Hoa Lam, Donato DiMonte, Nigel Maidment
The proSAAS chaperone is a low molecular weight, abundant secretory protein
which is expressed by neurons within the brain. Prior work has demonstrated
that proSAAS contains an internal anti-aggregant chaperone domain which
blocks the oligomerization of Abeta1-42 and α-synuclein. We have also shown
that proSAAS overexpression blocks α-synuclein-induced cytotoxicity in
primary cultures of nigral dopaminergic neurons. To assess whether secreted
proSAAS can also block α-synuclein spread and protect neuronal function in
vivo, we have determined whether virally-mediated proSAAS overexpression
can 1) attenuate the transsynaptic spread of α-synuclein; and/or 2) can block
motor asymmetry in an α-synuclein overexpression model of Parkinson’s
disease.
Methods: To examine transsynaptic spread, we administered α-synuclein
AAV into the vagus of mice in the presence of AAVs encoding either GFP
or proSAAS. After 6 weeks, we quantified the spread of α-synuclein positive
neurites into rostral nuclei using immunohistochemistry; this assessment
was carried out blinded. To examine proSAAS effects on Parkinson’s motor
symptoms, we administered either proSAAS- or GFP-encoding lentivirus
together with a--synuclein AAV unilaterally into the substantia nigra of rats.
Motor asymmetry was assessed using a battery of tests (cylinder, forelimb
placement and forelimb bracing) across 6 weeks in a double-blind fashion.
Results: We found that there was significantly less spreading of synuclein
into the pons and caudal midbrain in mice which received proSAAS AAV
as opposed to GFP-encoding AAV. In addition, motor asymmetry was
dramatically attenuated in rats receiving AAV α-synuclein together with
proSAAS-encoding lentivirus, as compared to those receiving AAV α-synuclein
with GFP-encoding lentivirus.

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Conclusions: We conclude that proSAAS overexpression is able to blunt
the synaptic spread of α-synuclein from the vagus into other brain regions,
suggesting that this chaperone may naturally function in the intrasynaptic space.
Further, intranigral overexpression of proSAAS exerted a profound protective
effect in a rat Parkinson’s model. We hypothesize that the marked improvement
in motor skills resulting from nigral proSAAS expression is due to its protective
effects on the catecholaminergic nigral-striatal pathway.

WEDNESDAY, JANUARY 29, 2020 • 3:30 P.M. - 4:30 P.M. • JEFFERSON/MADISON

W1. Heterogeneity in Ventral Striatal Subregion Encoding

of Reward Taking and Seeking
Katherine Wright*, Jennifer Teixeira, Daniel Wesson
The ability to execute goal-directed behavior requires the coordination of
sensory inputs with motivational states. The ventral striatum serves as a site
of convergence from cortical and midbrain dopaminergic inputs to evaluate
multimodal sensory stimuli and reward valuation, respectively, to inform and
select the appropriate behavior. The ventral striatum is comprised of the nucleus
accumbens (NAc) and the olfactory tubercle (OT). The NAc is well-established
for its role in motivation to take and seek out reinforcing compounds, and
recent work from our lab has established the OT’s representation of goal-
directed behavior and reward value. However, no evidence exists for the role of
the OT in reward taking and seeking. Therefore, the overall goal of this study
is to distinguish between NAc and OT encoding of reward-taking and reward-
seeking. To do this, we acquired multi-site single-unit activity as C57BL/6J
mice engaged in an operant sucrose self-administration task followed by
extinction and cue-induced reinstatement. In both the NAc and OT we found
populations of neurons whose firing patterns were dynamically modulated
upon either or both the instrumental response and the consummatory phases,
as well as modulation of firing during reward-seeking behavior. Future work
will further investigate the dynamics of these populations of neurons to identify
neural representations of different aspects of reinforcement and reward taking
and seeking, thereby contributing to a more complete understanding of the
ventral striatum and neural systems integral in the reward system.
R01DC014443, R01DA049545 to D.W.

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W2. Defining How Information Encoding in D1 and D2
Medium Spiny Neurons in the Nucleus Accumbens Guides
Motivated Behavior
Jennifer Zachry*, Munir Gunes Kutlu, Patrick Melugin, Liorimar Ramos-Medina,
Sophie Halpert, Erin Calipari
Value-based decision-making is at the core of nearly all motivated behaviors
and requires the ability to associate outcomes with specific actions and make
adaptive decisions about future behavioral action. Research has focused on
outlining the neural circuits that underlie this process and defining how the
neural activity within defined cellular subpopulations relates to the execution
of adaptive behaviors. At the core of value-based decision-making and
reinforcement is the nucleus accumbens (NAc) which is integrally involved
in learning, selecting, and executing goal-oriented behaviors. The NAc is
a heterogeneous population primarily composed of D1 and D2 medium
spiny projection (MSN) neurons that are thought to have opposing roles in
behavior with D1 MSNs promoting reward and D2 MSNs promoting aversion.
However, currently, our understanding of what these populations encode is
largely based on optogenetic studies that activate or inhibit these neuronal
populations to define how this promotes or inhibits ongoing behavior. By
expressing channelrhodopsin selectively in D1- and D2- populations (using
D1-Cre and A2A-Cre mice) in the NAc core, we show that mice will nose poke
for optical self-stimulation of both cell types, suggesting D2-MSN activity is
not inherently aversive. While optogenetic approaches give some information
about how cellular activation can modulate behavior, they eliminate the
temporally specific neural activity patterns that encode information in behaving
animals. To understand how real-time activity in these populations is linked to
behavioral execution, we expressed the genetically encoded calcium indicator
(GCaMP6f) within D1 and D2 MSNs coupled with in vivo fiber photometry
to record from these cell populations in awake and behaving animals during
operant conditioning tasks. Utilizing complex reinforcement schedules that
allow dissociation of stimulus value, outcome, cue learning, and action, we show
that D1 MSNs respond to the presence and intensity of unconditioned stimuli –
regardless of value. Conversely, D2 MSNs respond to a mismatch between what
is expected and what is received and thus encode errors in prediction in a value-
independent fashion. We provide foundational evidence for the discrete aspects
of information that are encoded within these cellular populations.

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W3. Chronic Opiate Exposure Alters Mesolimbic
Dopamine and Social Behavior
Marc Pisansky*, Emilia Lefevre, Sam Hochberger, Patrick Rothwell
Opiate abuse constitutes a significant public health issue, with overdose
mortality rates in the United States approaching ~47k cases annually (Center
for Disease Control & Prevention). The abuse liability of opiate drugs has
been hypothesized to stem in part from dopamine signaling within the
nucleus accumbens (NAc), as well as neuroadaptations throughout the
mesolimbic dopamine system. Interestingly, animal studies have reported
diverse behavioral and dopaminergic outcomes dependent on the pattern and
extent of opiate exposure. Our laboratory has previously found that chronic,
continuous morphine administration in mice produces psychomotor tolerance,
whereas interruption of this regimen produces psychomotor sensitization.
Here, we examined the effects of continuous versus interrupted (via twice-
daily naloxone injections) or intermittent (daily morphine injections) opiate
exposure on dopamine signaling within the NAc using dLight, a genetically-
encoded fluorescent biosensor. In vivo recordings of NAc core dopamine
were conducted in male and female mice early and late during continuous
or interrupted/intermittent morphine exposure, as well as during acute
challenges. Using optogenetics, we furthermore examined the effects of chronic
morphine exposure on evoked dopamine release from tegmental terminals
in the NAc. Lastly, we evaluated the effects of chronic morphine exposure
on social behaviors, namely dyadic social interaction and social novelty. Our
findings suggest that different patterns of chronic opiate exposure produce
divergent consequences in functioning of the mesolimbic dopamine system and
deleterious effects on naturalistic reward behaviors.

W4. Cocaine Extinction Induces Dendritic Spine

Alterations in Projection-Specific Subpopulations in the
Rat Infralimbic Cortex
Kelle Nett*, Sara Romig-Martin, Jason Radley, Ryan Lalumiere
Prior studies suggest ventral medial prefrontal cortex (mPFC), known as the
infralimbic cortex (IL), mediates the extinction and inhibition of cocaine
seeking, particularly through projections to the nucleus accumbens (NA) shell.
Previous work from our laboratory indicates cocaine self-administration, but
not passive receipt of cocaine, induces regressive plasticity within the dorsal
mPFC, as indicated by dendritic spine density reductions of pyramidal neurons.
These results suggest an intersection between cocaine itself and the learned
instrumental behavior in terms of prefrontal plasticity alterations. However,
it is unclear whether similar changes occur in the IL and whether extinction
training further alters dendritic plasticity in the IL. Moreover, it is unclear

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whether behavior affects global dendritic plasticity within the IL or specific
subpopulations of projection neurons. To address this issue, Sprague-Dawley
rats (250-275 g) received bilateral microinjections of a retrograde adeno-
associated virus containing a GFP tag into the NAshell and were implanted with
intrajugular catheters. Rats then underwent 2 wks of daily 6 h cocaine self-
administration, in which active lever presses produced a cocaine infusion (400
μg/infusion) and light/tone cues. Rats then underwent 2 wks of extinction
training (1 h / d), in which active lever presses had no consequence, or 2 wks of
homecage withdrawal, prior to being euthanized. We then used an intracellular
dye cell-loading technique to fill NA shell-projecting IL pyramidal neurons with
Lucifer yellow. Neurons were imaged with 3D confocal imaging followed by
deconvolution and analysis using NeuronStudio software. Preliminary results
suggest extinction selectively alters dendritic spine density and clustering,
specifically in IL→NAshell neurons. These findings point to an important
interaction between cocaine self-administration and behavioral encoding that
influences structure in a subpopulation-specific manner.

W5. Sex Differences in Behavioral Strategies are

Accompanied by Altered Neural Circuit Dynamics in
Ventral Tegmental Area to Nucleus Accumbens Projections
Amy Johnson*, Suzanne Nolan, Emily Chuang, Jennifer Zachry, Munir Kutlu, Erin
Calipari
Women are more vulnerable than men to a number of psychiatric disease states
including depression, anxiety, and substance use disorder; however the large
majority of studies in these fields have focused on male subjects making studies
understanding how these processes occur in females imperative to women’s
health. It has been hypothesized that sex differences in neuropsychiatric
disorders are manifestations of differences in basic reward processing. Thus,
our goal was to understand sex differences in these processes as well as identify
the neural basis of these differences. By combining a novel behavioral task
– designed to dissociate motivated action from cue learning and valence –
with in vivo fiber photometry calcium imaging in the ventral tegmental area
(VTA) and nucleus accumbens (NAc) we identified the sex-specific activity
signatures that underlie this process. First, we showed that female mice self-
administer higher levels of sucrose but acquire negative reinforcement at a
slower rate, highlighting the importance of stimulus value in the expression
of sex differences in learned behavior. Further, in situations where positive
and negative stimuli are presented together, females favor avoiding aversive
outcomes over seeking rewards. Interestingly, we did not see sex differences
in the activity of the VTA to NAc pathway to the initial exposure to positive
(sucrose), negative (footshock), or neutral (random cue) stimuli; however,
differences emerged later as animals had successfully acquired each task. Our

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results highlight that stimulus specific learning is an important factor in the
expression of sex differences and shows the importance of understanding
context-specific behavior when making conclusions about sex-specific strategies
and their neural control.

W6. Effect of Lateral Hypothalamus Excitotoxic Lesions on

the Acquisition of Sign-Tracking Behavior
Cristina Maria Rios*, Jonathan Morrow
Cue-reward associations are critical for developing adaptive responses that
promote survival. However, reward-associated cues can sometimes acquire
excessive motivational value, resulting in maladaptive behaviors such as those
associated with addiction and relapse. Individual differences in Pavlovian
conditioned approach (PCA) behavior can be used to disentangle the
predictive and motivational properties of associative cues. “Sign-tracking”
rats will reliably approach a reward-associated cue and interact with it,
indicating that the cue itself has acquired incentive-motivational value for these
individuals. In contrast, “goal-tracking” rats direct their conditioned behavior
away from the cue and towards the site of impending food reward, indicating
that they are using the cue solely as a predictor of the reward, but the cue itself
has not acquired motivational value for them. Although these behaviors have
been well-characterized, the neurocircuitry responsible for biasing sign- and
goal-tracking behavior is not well understood. Sign-trackers show increased
c-fos activity in regions like the lateral hypothalamus in response to a reward
cue, and blocking orexinergic transmission to the paraventricular nucleus of the
thalamus disrupts sign-tracking behavior and motivational salience attribution.
Because the lateral hypothalamus is a major source of orexin signaling in this
region, we excitotoxically lesioned the lateral hypothalamus of rats and tested
the acquisition of sign- and goal-tracking. We found that lesioned rats showed
reduced acquisition of sign-tracking behavior compared to sham controls, while
goal-tracking was unaffected. These data indicate that lateral hypothalamus
activity may play a role in attributing motivational value to reward cues. Further
dissection of the neurocircuitry Responsible for biasing these behaviors could
provide insight into why some individuals are more vulnerable than others to
addiction and other neuropsychiatric disorders.

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W7. Investigating the Role of Glucocorticoid Receptor
Activation in the Propensity to Attribute Incentive Value to
Reward Cues
Sofia Lopez*, Youngsoo Kim, Robert Kennedy, Shelly Flagel
Through associative learning, environmental cues become predictors of relevant
stimuli (e.g. food). When such cues, however, are attributed with excessive
incentive value they gain inordinate control and elicit aberrant behavior. For
example, individuals with addiction often relapse when they encounter drug-
associated cues, despite the desire to remain abstinent. Using an animal model
that captures individual variation in the propensity to attribute incentive value
to cues, we are able to examine the neurobiology that contributes to such
psychopathology. Following Pavlovian training, rats may develop either a sign-
or goal-tracking response. While both sign-trackers (ST) and goal-trackers
(GT) attribute predictive value to a food cue, ST also attribute incentive value.
Different brain circuits are engaged in response to the cue in ST vs. GT, with
dopamine (DA) in the nucleus accumbens (NAc) necessary for incentive, but
not predictive, learning. DA interacts with corticosterone (CORT), a primary
regulator of the stress response, to mediate motivated behaviors. CORT acts
upon glucocorticoid receptors (GR) and increases NAc DA. Yet, little has
been done to investigate DA-CORT interactions in the context of ST and
GT. Here we assessed the effect of CORT on sign-tracking and DA during
Pavlovian learning. 3 mg/kg of CORT or vehicle was administered (i.p.) to
male and female rats prior to Pavlovian conditioning sessions. DA samples were
obtained via in vivo microdialysis within the NAc during the first (1) and last
(6) sessions. CORT administration resulted in an increase in the acquisition of
sign-tracking behavior, and enhanced the conditioned reinforcing properties
of a discrete food-cue, but to a different degree and male and female rats. In
support of the behavioral findings, we hypothesize that NAc DA will increase
in response to CORT. These data highlight a role for CORT in DA-dependent
learning processes that are relevant to cue-driven psychopathologies.

W8. CRISPR/Cas9 Editing of Neuropeptide Receptor

Signaling Reveals an Extended Amygdala Circuit
Mechanism Modulating Alcohol Drinking, Anxiety, and
Avoidance
William Giardino*, Hiroshi Yamaguchi, Luis de Lecea
Negative emotional states linked to addiction arise from neuroplasticity
within neuronal networks of the hypothalamus and amygdala. These circuits
encompass an enormous diversity of cell types that display specialized
connectivity patterns and innumerable forms of signaling. Specifically, lateral
hypothalamus (LH) neurons containing the neuropeptide Hypocretin (Hcrt;

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orexin) profoundly influence arousal (wakefulness) and motivated behavior.
I previously identified connectivity between Hcrt-LH neurons and “extended
amygdala” neurons of the bed nuclei of stria terminalis (BNST) containing
the prototypical stress peptide corticotropin-releasing factor (Crf). I then
characterized Hcrt-LH and Crf-BNST neurons as tightly coupled nodes in a
stress-promoting circuit, suggesting their involvement in addiction.
Here, I investigated Hcrt-LH neurocircuits in free-choice binge alcohol
drinking by performing genetically defined physiological monitoring, optical
manipulations, and molecular perturbations in neurons of freely-behaving mice.
First, I identified Hcrt-LH activation during alcohol withdrawal-enhanced
anxiety behavior, and used in vivo Ca2+ recordings to reveal withdrawal-
dependent sensitivity of Hcrt-LH neurons to aversive stimuli. I next revealed
the necessity of Hcrt for behavioral avoidance driven by Crf-BNST stimulation,
and focused on BNST-projecting Hcrt-LH neurons with the hypothesis
that BNST Hcrt receptors drive excessive alcohol drinking. We developed a
CRISPR/Cas9 gene editing system, finding that disruption of HcrtReceptor1
(hcrtr1) in Crf-BNST neurons reduced alcohol intake, anxiety, and avoidance.
These studies advanced prior work by identifying the mechanisms through
which LH→BNST circuits promote excessive alcohol consumption. We posit an
essential role for Crf-BNST-HcrtR1 signaling in alcohol addiction via negative
emotionality and dysregulated hyperarousal. These outcomes have major
implications for developing effective strategies to treat addiction.

W9. Rat Self-Administration of Toluene Vapor

Kevin Braunscheidel*, Wesley Wayman, Michael Okas, John Woodward
Inhalants, including volatile organic solvents (e.g. toluene), continue to be one
of the most prevalent, and often first substances abused by adolescents. Like
other drugs of abuse, toluene affects the function of neurons within key brain
reward circuits including the prefrontal cortex, ventral tegmental area and
nucleus accumbens. However, preclinical models used to study these toluene-
induced adaptations generally employ passive exposure paradigms that do not
mirror voluntary patterns of solvent exposure observed in humans. To address
this shortcoming, we developed an inhalation chamber containing active
and inactive nose pokes, cue lights, flow-through vaporizers, and software-
controlled valves to test the hypothesis that rats will voluntarily self-administer
toluene vapor. Following habituation and self-administration (SA) training
rats achieve vapor concentrations associated with rewarding effects of toluene,
and maintain responding for toluene infusions, but not for air infusions.
During extinction trials, rats showed an initial burst of drug-seeking behavior
similar to that of other addictive drugs and then reduced responding to air
SA levels. Responding on the active nose poke recovered during cue-induced

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reinstatement but not following a single passive exposure to toluene vapor. The
results from these studies establish a viable toluene SA protocol that will be
useful in assessing toluene-induced changes in addiction neurocircuitry.

W10. Activation of the Estradiol Receptor, GPER1,

Attenuates Preference for Cocaine in Male, but Not in
Female Rats
Jacqueline Quigley*, Jill Becker
There are sex differences in susceptibility to addiction. Female rodents are more
motivated to take cocaine and acquire a preference for cocaine at lower doses
than males. More females also prefer cocaine to natural rewards, compared
to males. Research from the Becker Laboratory found that these heightened
addiction-like behaviors in females are modulated by estradiol, where estradiol
potentiates cocaine-induced dopamine levels in the dorsal striatum (dSTR)
and motivation for cocaine. Here we report that estradiol also modulates drug
preference and motivation for cocaine in males, but in a way that is different
from females. The current study investigated the effects of estradiol receptor
(ER) manipulation on the preference for cocaine in male and female rats by
administering selective ER agonists or antagonists intra-dSTR. We found that
in males, ICI182,780 (ERα/β antagonist; GPER1 agonist) or G1 (GPER1
agonist) blocked preference for 10mg/kg cocaine, as measured by conditioned
place preference (CPP). Treatment with G15 (GPER1 antagonist) intra-dSTR
enhanced preference for 5mg/kg cocaine in males, control males did not
acquire CPP at this dose. Neither ICI nor G1 altered female’s CPP for cocaine.
These data suggest that GPER1 regulates preference for cocaine in males only.
We then investigated potential sex differences in ER expression in the dSTR
between male and female rats using qPCR, no significant difference in ERα,
ERβ or GPER1 expression between the sexes was found. Our final experiment
investigated whether estradiol was being synthesized locally within the dSTR
to affect CPP by using an aromatase inhibitor (exemestane) to prevent the
synthesis of estradiol from testosterone. Intra-dSTR exemestane had no effect
on CPP for cocaine in either sex. These data support the notion that these are
sex differences in how ERs alter the rewarding properties of drugs of abuse:
enhancing motivation in females while attenuating motivation in males.

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W11. Sex Differences in Cholinergic Regulation of
Local Nucleus Accumbens Circuit Function Controlling
Motivation
Lillian Brady*, Jennifer Tat, Jennifer Zachry, Alberto Lopez, Munir Kutlu, Erin
Calipari
Considerable progress has been made toward our understanding of psychiatric
disease states over recent years; however, a majority of these studies have
primarily focused on male subjects. In psychiatric conditions characterized by
abnormalities in motivation and reward processing - such as substance abuse
disorder - sex is a critical biological variable and women represent a particularly
vulnerable population. The lack of data describing the unique neural circuitry
underlying these sexual dimorphisms highlight a critical need for preclinical
investigation of reward learning and motivation in female subjects. A variety of
factors could be contributing to these sex differences – including estrous cycle
dependent ovarian hormone fluctuations - but the precise neurobiological
mechanisms underlying these differences in reward and motivation are largely
unknown. An essential component of the process that controls motivation and
reward-seeking behavior is the mesolimbic dopamine pathway, connecting the
ventral tegmental area to the nucleus accumbens (NAc). In the NAc, dopamine
is released in a tonic/phasic frequency and is heavily modulated by nicotinic
acetylcholine receptors (nAChRs) of the cholinergic system located both on
dopamine terminals and on other cellular populations within the NAc. Using
fast-scan cyclic voltammetry and site-specific pharmacology we measured
subsecond dopamine kinetics in male and female mice in either diestrus (low
circulating hormones) or estrus (high circulating hormones) and defined
sex-differences in local cholinergic regulation of dopamine release in the
NAc. We show a differential effect of the nAChR blocker mecamylamine on
presynaptic dopamine release in males and females regardless of cycle stage,
suggesting a differential organization of cholinergic regulation of NAc circuitry
between the sexes. Together this work will expand our understanding of the sex
differences in cholinergic regulation of local NAc circuit function underlying
reward learning, aiding in the development of better and more effective
pharmacotherapies to counter psychiatric disease states in women.

W12. Beta-Caryophyllene: A Novel Therapeutic Approach

for Cocaine Use Disorder
Ewa Galaj*, Guo-Hua Bi, Eliot Gardner, Zheng-Xiong Xi
Cocaine use disorder (CUD) continues to be a serious health problem
worldwide. Despite intense research, there is still no FDA-approved medication
for it. Recent efforts to discover potential effective therapeutics have focused on
the endocannabinoid system because of its identification as a neurobiological

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substrate underlying drug addiction. In the last decade, there has been growing
interest in beta-caryophyllene (BCP), a volatile phytocannabinoid present
in high proportions in cannabis and large numbers of spice and food plants.
This dietary additive, which possesses a CB2 receptor agonist profile, has been
shown to produce promising therapeutic effects for multiple neuropsychiatric
disorders. Surprisingly, a therapeutic potential of BCP in the treatment of drug
abuse and addiction has not been explored. Here, using gold standard animal
models of drug abuse, we systematically evaluated the potential therapeutic
utility of BCP against cocaine-related behaviors. In a series of experiments,
we found that BCP attenuated cocaine-enhanced electrical brain-stimulation
reward in rats and optogenetic intracranial self-stimulation driven by activation
of dopamine (DA) neurons in DAT-cre mice, both outcomes indicating
reduced reward efficacy and, by extension, reduced cocaine abuse liability.
Intriguingly, when administered systemically or orally, BCP attenuated cocaine
self-administration in rats, again demonstrating its ability to reduce cocaine
abuse. BCP also reduced drug-primed reinstatement of cocaine seeking and
cocaine conditioned place preference, indicative of its preventative effects
against relapse. When BCP was substituted for cocaine, rats ceased responding,
suggesting BCP itself has low liability abuse. These findings concur with our
in vivo microdialysis data showing that BCP alone failed to alter extracellular
DA in nucleus accumbens. Our findings suggest that BCP shows exceptional
promise as a therapeutic candidate in the treatment of CUD. Importantly,
given its good oral bioavailability and the advantage of being an already FDA-
approved non-toxic dietary additive, BCP is a valuable candidate for drug
repurposing programs in translational medicine.

W13. Ethanol Induced Concentration-Dependent Effects

on POMC Neuronal Excitability
Jonna Jackson*, Erin Nagy, Lauren Hood, M. Foster Olive
Alcohol abuse is a worldwide public health concern and leads to an estimated
90,000 alcohol-related deaths in the United States annually. Recent evidence
suggests that alcohol may promote its euphoric and motivational effects, in
part, by activating the endogenous opioid system. Further supporting the role
of the endogenous opioid system in alcohol abuse, one of the most frequently
utilized medications for treating alcohol use disorders to date is naltrexone,
a broad spectrum opioid receptor antagonist. One particular circuit of the
endogenous opioid system consists of pro-opiomelanocortin (POMC)
producing neurons in the arcuate nucleus (ArcN) of the hypothalamus,
which project heavily to reward-related areas. To identify the physiological
effects of ethanol on POMC neurons, we utilized whole cell patch-clamp
recordings of POMC neurons from POMC-EGFP mice and bath application
of ethanol (5-40 mM) to identify alterations in (1) spontaneous baseline

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activity, (2) spike threshold/rheobase, (3) spiking characteristics or (4)
intrinsic properties. Using whole-cell electrophysiology, we found that bath
application of low concentrations of ethanol (10mM) increased the number
of spikes in response to a depolarizing current in a majority of recorded cells.
Additionally, in a majority of recorded cells, higher concentrations of ethanol
(20-40mM) decreased the number of spikes in response to a depolarizing
current. While ethanol changed the number of depolarization elicited spikes
in a concentration-dependent manner, compared to control, rheobase was
unaffected regardless of ethanol concentration. Additionally, spontaneous
POMC activity, measured by spontaneous excitatory post-synaptic potentials
(EPSPs) at rest were also unchanged in response to ethanol. Interestingly, 5mM
ethanol had no effect on the number of spontaneous EPSPs, but significantly
decreased the EPSP amplitude. Together, these results suggest that ethanol has
concentration-dependent modulatory effects on POMC neuronal physiology.
To our knowledge, these are the first studies to characterize the physiological
effects of ethanol on POMC-neurons of the hypothalamus and may lend insight
into treating alcohol use disorders.

W14. Modeling Motivation for Alcohol in Humans Using

Traditional and Machine Learning Approaches
Erica Grodin*, Amanda Montoya, Spencer Bujarski, Lara Ray
Background: Prolonged alcohol use can result in alcohol use disorder (AUD),
a chronic relapsing disorder that is often untreated. Individual variability in the
development of AUD likely reflects the interaction between chronic use, as well
as biological, psychosocial, and environmental risk factors. It remains unknown
what variables are associated with alcohol self-administration (SA) phenotypes,
which themselves may reflect risk factors.
Methods: Non-treatment-seeking heavy drinkers (n=67) completed an
IV alcohol administration paradigm combining an alcohol challenge and a
progressive ratio alcohol SA. Growth curve analysis was used to identify SA
phenotypes. Two analyses were conducted identify variables that predicted
cluster membership. First, a logistic regression was conducted using a-priori risk
factors (sex, family history, and delay discounting). Second, a series of random
forest models were run to identify clinical predictors.
Results: Two SA phenotypes were identified: (1) motivated, in which
participants continued to work for alcohol throughout the session (n=41); and
(2) unmotivated, in which participants exhibited limited motivation to work for
alcohol (n=26). In the logistic regression, only delay discounting impulsivity
significantly predicted SA phenotype (B=-0.54, SE=0.23, χ2=5.50, p=0.02).
The two most important variables identified by the random forests were phasic
craving for alcohol and delay discounting.

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Conclusion: Clinical characteristics can predict alcohol SA phenotypes. Higher
delay discounting, indicating a preference for smaller, sooner over larger, later
rewards, was predictive of motivation to work for alcohol in both approaches.
The data-driven approach indicated that greater phasic craving during the
challenge was predictive of the motivated phenotype. These results indicate
that using data-driven approaches to investigate alcohol motivation represents a
promising tool to identify individual vulnerability for the development of AUD.

W15. Targeted Epigenetic Editing in the Amygdala

Prevents Adulthood Behavioral Pathology Caused by
Adolescent Alcohol
John Bohnsack*, Huaibo Zhang, Donna He, Amy Lasek, Subhash Pandey
Alcohol use disorder (AUD) is a chronic, debilitating psychiatric disease that
afflicts 6% of the US population and is responsible for 88,000 deaths per year.
Adolescent alcohol consumption increases the risk of developing an alcohol use
disorder by 5-7 times and comorbid anxiety. Recent advances in the field have
suggested that epigenetics plays an important role in transition from adolescent
alcohol consumption to the development of an AUD later in life, however
probing the specific behavioral and endophenotype outcomes that arise
because of epigenetic dysregulation by adolescent alcohol consumption are still
largely unknown.
We recently identified that an enhancer region upstream of the activity-
regulated cytoskeleton-associated protein (Arc) gene, the synaptic activity
response element (SARE) site, undergoes substantial epigenetic remodeling
after adolescent alcohol exposure that persists until adulthood in rodents
and humans. We utilized a dCas9-P300 strategy to probe if restoring histone
acetylation associated with the Arc SARE site would prevent behavioral changes
induced by adolescent exposure.
We exposed adolescent rats to intermittent ethanol then allowed them to
mature to adulthood. Infusion of dCas9+sgRNAs in the central nucleus of the
amygdala prevented elevated anxiety-like behavior, decreases in Arc expression,
and decreased H3K27Ac associated with the Arc SARE site. We observed no
off-target effects.
Our results indicate that restoring H3K27Ac at the Arc SARE site prevents
anxiety-like behavior and decreased Arc expression. Arc is a critical regulator
of synaptic plasticity and has long been known to be a hub gene in controlling
changes after AIE that persist until adulthood. This suggests the usefulness of
dCas9 strategies for evaluating discrete regions in the epigenome to determine
their functional consequences which may lead to the development of better
therapeutics for the treatment of early onset alcohol use disorders.

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W16. Cell Type Specific Role of HDAC3 Within the NAc in
Regulating Cocaine-Induced Plasticity
Rianne Campbell*, Yousheng Jia, Joy Beardwood, Lilyana Pham, Agatha
Augustysnki, Alberto Lopez, Dina Matheos, Gary Lynch, Marcelo Wood
Cocaine utilizes mechanisms of synaptic plasticity and transcription within the
nucleus accumbens (NAc) to promote drug-seeking behaviors. Recent work
from the field demonstrates that this occurs in a cell-type specific manner, often
differentially affecting mechanisms of plasticity within the two major output cell
types of the NAc: dopamine D1- (D1R) vs D2-receptors (D2R) medium spiny
neurons (MSNs)1–3. Consistent with this, activation of D1R- and D2R- MSNs
drive opposing behavioral responses to cocaine4. However, it is unclear how
cocaine affects epigenetic mechanisms within D1R- vs D2R- MSNs to promote
cocaine-associated behaviors5,6. Prior work from our lab demonstrates that
cocaine disengages histone deacetylase 3 (HDAC3) within the NAc to promote
cocaine-induced gene expression and cocaine-associated memory formation7,8.
Here, we have investigated the specific role of HDAC3’s deacetylase activity
in cocaine-induced behaviors and cellular activity within the NAc8. More
specifically, we have observed the expression profile of HDAC3 following
cocaine exposure within these two MSN cell types. In addition, we have found
that disrupting HDAC3’s activity using Cre-dependent viral vectors within
D1R-MSNs, but not D2R-MSNs, affects cocaine-induced conditioned place
preference. In addition, we have studied the effects of blocking HDAC3 activity
on cell-type specific changes in cocaine-induced synaptic plasticity within D1R
vs D2R-MSNs. Together, these results illustrate how cocaine alters mechanisms
of histone acetylation to induce cell-type specific changes in synaptic plasticity
that promote drug-associated behaviors.

W17. Epigenetic Priming Underlies Transcriptional

Disruption Linked to Cocaine Relapse
Philipp Mews*, Hope Kronman, Aarthi Ramakrishnan, Abner Reyes, Simone
Sidoli, Benjamin Garcia, Li Shen, Eric Nestler
Drug addiction is a major public health crisis that exacts tremendous
psychological and financial costs on patients, their families, and society at
large. Drugs of abuse, despite their very different chemical structures and
initial protein targets, ultimately converge by producing persistent plasticity
and long-lasting changes in gene regulation in a central brain region of reward,
the nucleus accumbens (NAc). Permanent changes in chromatin structure are
hypothesized to underlie the transcriptional dysregulation that characterizes
drug addiction; however, there is to date no direct link between drug-induced
epigenetic alterations and the aberrant gene regulation that contributes to
relapse. A fundamental challenge is to determine which neuronal subtypes are
responsible: the NAc is composed of two opposing types of medium spiny

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neurons (MSNs), the D1 and D2 dopamine receptor-expressing subtypes,
which exhibit dramatic differences in activity and effects on drug reward.
Here, we investigated the cocaine-induced changes in chromatin genome-wide
by ATAC-seq in the distinct D1 and D2 MSN subtypes, and distinguished
immediate versus persistent alterations in combination with unbiased histone
modification profiling by mass spectrometry and ChIP-sequencing. We found
that chronic cocaine persistently alters striatal chromatin structure, especially in
D1 MSNs, involving eviction of the histone variant H2A.Z, a recently identified
memory suppressor, at key neuronal genes. Curiously, genome accessibility in
D1 MSNs is prominently increased at these ‘scarred’ genes even after prolonged
periods of withdrawal, linked to long-lasting dysregulation of gene expression
upon relapse. Together, our studies investigate an emerging view of epigenetic
adaptation and gene dysfunction that may contribute to drug addiction,
providing novel insight into epigenetic priming as an important mechanism
whereby drugs of abuse alter brain function and behavior in lasting ways. Since
epigenetic aberrations may be reversible, this mechanistic understanding of
chromatin ‘scarring’ by drugs of abuse could pave the way to novel epigenetic
interventions to treat drug addiction.

W18. Endocannabinoid Signaling in a Septohabenular

Circuit Regulates Anxiety-Like Behavior
Casey Vickstrom*, Xiaojie Liu, Laikang Yu, Shuai Liu, Yan Li, Ying Hu, Cecilia
Hillard, Qing-song Liu
The endocannabinoid (eCB) system can mediate anxiolysis, and exogenous
cannabinoid agonists (e.g. Δ9-tetrahydrocannabinol) are frequently used for
their anxiolytic effects. However, the neural circuits whereby cannabinoids exert
these effects remain incompletely identified. The medial habenula (MHb) is a
well-conserved epithalamic structure that is a powerful modulator of anxiety-
and mood-related behavior in rodents and zebrafish and has been shown by
MRI to be decreased in volume in humans with depression. We report in adult
male and female mice that the eCB 2-arachidonoylglycerol (2-AG) is released
from neurons of the MHb, and that this eCB release retrogradely suppresses
an atypical, excitatory GABAergic synaptic input from the medial septum and
nucleus of the diagonal band (MSDB) to the MHb. We show using viral-genetic
circuit mapping, optogenetics, and slice electrophysiology that the MSDB sends
a direct GABAergic projection to neurons of the ventral MHb. We observed
CB1 receptor-dependent depolarization-induced suppression of excitatory
GABA currents (DSE-GABA) as well as a CB1 agonist-induced suppression of
GABA postsynaptic currents in MHb neurons. Using optogenetics, we show
that this occurs at MSDB axon terminals in the MHb. Viral-genetic knockdown
of CB1 from MSDB neurons led to anxiety-like behavior in mice and abolished
DSE-GABA in the MHb, suggesting that 2-AG regulation of MSDB to MHb

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neurotransmission can produce anxiolytic behavioral effects. Thus, we have
likely identified a novel circuit mechanism whereby eCBs control anxiety-like
behavior.

W19. Psychostimulants Exert Dose Dependent Effects on

Frontostriatal Neuronal Signaling
Robert Spencer*, Andrea Martin, David Devilbiss, Rick Jenison, Craig Berridge
The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical
role in higher cognitive function with dysregulation implicated in a variety of
behavioral pathologies, including addiction and ADHD. Psychostimulants exert
potent dose-dependent cognitive actions. In high doses associated with abuse,
these drugs robustly impair PFC-dependent cognition. In contrast, low doses
used in the treatment of ADHD, improve PFC-dependent cognition. Currently,
our understanding of the neural coding bases for the diverse cognitive actions
of psychostimulants are unclear. Thus, we examined the effects of cognition-
impairing and cognition-enhancing doses of methylphenidate (MPH) on
neuronal spiking activity and local field potential (LFP) power spectral density
within the dorsomedial PFC (dmPFC) and dorsomedial striatum (dmSTR)
in rats performing a spatial working memory task. Within the dmPFC, a
cognition-impairing dose of MPH robustly suppressed the activity of neurons
strongly tuned to delay and reward, while activating neurons not tuned to
reward delivery. In contrast, in the dmSTR, cognition impairing doses of MPH
had no effect on neurons strongly tuned to task events, while robustly increasing
firing of neurons not strongly tuned to these events. Thus, cognition-impairing
doses strongly decrease the signal-to-noise representation of key task events.
Interestingly, cognition improving doses had little impact on task-related firing
of neurons in either region.
For LFP spectral density, MPH elicited a complex array of actions that were
region-, frequency- and dose-dependent. Interestingly, in the PFC, we saw
opposing actions of cognition improving vs. cognition impairing doses of
MPH on the ratio of theta power to both beta and gamma power. Specifically,
cognition enhancing doses increased while cognition impairing doses
suppressed these ratios. These ratios have been previously linked to both
cognitive function and PFC dysregulation. Lastly, delay-related PFC-STR
coherence in the gamma range was increased selectively by the cognition-
impairing dose of MPH.
These observations indicate that the cognition-improving vs. cognition-
impairing effects of psychostimulants target unique aspects of frontostriatal
neuronal coding.

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W20. Striatal Melanocortin-4 Receptor Influences Action/
Habit Balance in Mice
Elizabeth Heaton*, Aylet Allen, Lauren Shapiro, Shannon Gourley
Many neuropsychiatric diseases, including substance use disorder, are
characterized, in part, by a failure to flexibly adapt to an ever-changing
environment. This lack of behavioral flexibility often results in an overreliance
on habitual behavior at the expense of goal-directed action, i.e., habitually
using a substance to the detriment of progressing in a career. The dorsomedial
striatum (DMS) is essential for maintaining goal-directed behavior – it is
active during new task learning, and it is re-engaged when habits are “broken”.
However, the neuronal factors underlying an organism’s ability to flexibly toggle
between goal-directed and habit-based behavior are not completely understood.
We recently compared gene expression in the DMS between mice that could
and could not modify familiar instrumental behaviors. These and secondary
confirmation experiments revealed that lower levels of the melanocortin-4
receptor (MC4R) are associated with behavioral flexibility (breaking habits).
To identify functional consequences, we used viral-mediated gene silencing
to selectively reduce Mc4r in the DMS. Mc4r knockdown facilitated animals’
ability to select actions based on their consequences, resulting in increased
goal-directed behavior. Thus, reducing MC4R expression in the DMS is
sufficient to increase behavioral flexibility in mice. MC4R is well studied in the
hypothalamus, where its role in energy homeostasis is well understood, yet
comparatively little is known about MC4R function in the striatum, despite
robust expression. These results reveal for the first time that striatal MC4R
is a key factor in sustaining vs. “breaking” habits, with low levels conferring
behavioral flexibility.

W21. The Role of GIRK Signaling in Prefrontal Cortical

Regulation of Affect, Cognition, and Stress Pathology:
Implications for Therapeutic Targeting
Eden Anderson*, Steven Loke, Ben Wrucke, Annabel Engelhardt, Evan Hess, Kevin
Wickman, Matthew Hearing
Imbalance in prefrontal cortical (PFC) pyramidal neuron (PYR) excitation
and inhibition is thought to underlie behavioral symptomologies shared
across numerous neuropsychiatric disorders, including top-down control
of affect and flexible decision-making, that are also observed with chronic
unpredictable stress (CUS). We have previously shown that G protein-
gated inwardly rectifying potassium (GIRK) channels regulate the output
of medial PFC PYR output, however little is known regarding regulation of
cortical interneurons or the functional relevance of PFC GIRK signaling in
regulation of affect, cognition and cortical dynamics. Using a viral-mediated

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(Cre-dependent) approach in mice harboring a ‘floxed” version of the Girk1
gene we examined effects of disrupting GIRK1-containing GIRK channel
expression in PYR residing in the prelimbic (PrL) and infralimbic (IL) regions
of the mPFC. In males, loss of PYR GIRK signaling in the PrL but not IL
cortex differentially impacted measures of affect/motivation, and impaired
working memory and cognitive flexibility. Preliminary studies indicate that
loss of GIRK signaling in PL PYR in females has distinctly different effects on
behavior, as does constitutive loss of GIRK1 in parvalbumin expressing neurons
(interneurons). Similar deficits in affect and cognition were observed following
prolonged exposure to CUS, and that CUS produced a reduction in PrL PYR
GIRK signaling akin to viral approaches. Viral- and stress-induced behavioral
deficits were rescued by systemic injection of a novel, GIRK1-selective agonist,
ML-297. Together, GIRK signaling is critical for optimal mPFC cognitive
control. Further, disruption of GIRK signaling may underlie stress-related
dysfunction of the mPFC and associated psychopathologies and represent a
therapeutic target for treating stress-induced deficits in affect and one of the
most consistently documented deficits across neuropsychiatric disorders –
impaired cognitive flexibility.

W22. Striatal Dopamine Promotes Cognitive Effort by

Amplifying the Benefits Versus the Costs of Cognitive
Work
Andrew Westbrook*, Ruben van den Bosch, Jessica Määttä, Lieke Hofmans, Danae
Papadopetraki, Roshan Cools, Michael Frank
Stimulants like methylphenidate are increasingly used to treat ADHD-like
symptoms, and for cognitive enhancement, but the precise mechanisms of
action are unknown. Prior theories have alternately pointed to cortical or
subcortical effects and modulation of either dopamine or norepinephrine.
In this study, we show that striatal dopamine increases willingness to expend
cognitive effort for reward, by amplifying the subjective benefits versus the
subjective costs of action. Our study utilized convergent evidence including
PET measures of dopamine synthesis capacity, methylphenidate, and sulpiride,
a D2 receptor agent, to implicate striatal dopamine, in particular. Gaze patterns
reveal that attention to benefit versus cost information also promotes cognitive
motivation. Furthermore, both methylphenidate and higher dopamine
synthesis capacity increase the effect of benefits on the evidence accumulation
process. In addition, we find dynamic effects of gaze on choice, where gaze early
in a trial magnifies the influence of attended-versus-unattended information
while late gaze instead reflects an emerging preference. These findings help
resolve conflicting accounts of how gaze impacts economic decision-making
more broadly, beyond decisions about cognitive effort.

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W23. MRI-Guided Focused Ultrasound and rAAV2-HBKO
Lead to Widespread Expression of Transgene in the Brain
Rikke Kofoed*, Kate Noseworthy, Kelly Markham-Coultes, Lisa Stanek, Bradford
Elmer, Lamya Shihabuddin, Kullervo Hynynen, Isabelle Aubert
Disorders of the central nervous system (CNS) such as Alzheimer’s disease,
Parkinson’s disease, and amyotrophic lateral sclerosis have no cure. Gene
therapy holds the promise to provide long-lasting clinical benefits for these
neurodegenerative disorders following a single administration. However, adeno-
associated viral vectors (AAVs), commonly used for gene therapy, do not easily
bypass the blood-brain barrier (BBB) and efficient AAVs delivery to the CNS
requires either very high doses or invasive surgery. Pioneer work at Sunnybrook
has established that MRI-guided focused ultrasound (MRIgFUS) can safely,
transiently and non-invasively increase the permeability of the BBB in targeted
areas of the brain and spinal cord preclinically; and clinically, in brain regions
affected in patients with Alzheimer’s disease and ALS.
For gene therapy, MRIgFUS offers the advantage to deliver AAVs, administered
intravenously at a relatively low dose, to specific areas of the CNS. Here, we
used the AAV2-HBKO, known for its enhanced tissue distribution compared to
AAV2, with the goal of increasing the number of transduced cells in MRIgFUS-
targeted brain regions. The brain regions selected in mice are relevant to those
affected in human with neurodegenerative disorders.
Our results demonstrate that the AAV2-HBKO delivered by MRIgFUS to
specific regions of the mouse brain (eg striatum) transduces cells beyond
the focal size targeted. In addition, widespread transgene expression was
observed through neuronal connections (eg striato-nigral pathway). Transgene
expression in off-target areas was also investigated.
Our findings represent a new gene therapy strategy with a single, localized, and
non-invasive delivery to the brain resulting in high and long-term transgene
expression reaching multiple regions. Future studies will focus on using
this approach for expression of therapeutic transgenes in animal models of
neurodegenerative diseases and determine its use for scalability to human.

W24. Angiotensin II Signaling Potentiates GABA(A)

Receptor Activity of GABAergic Pars Reticulata Projection
Neurons
Ratan Singh*, Gregory Amberg, Jozsef Vigh
At least 70% of the synapses formed on midbrain dopaminergic neurons
are GABAergic and the axon collaterals of the GABAergic substantia nigra
pars reticulata (SNr) projection neurons acts most consistently to inhibit
dopaminergic neurons in vivo. Angiotensin II (Ang II) is a well-characterized
regulator of cardiovascular function in the periphery but it is also found in

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the central nervous system where local concentrations can exceed those
found in the circulation. Ang II signaling is known to modulate GABAergic
neurotransmission in the median preoptic nucleus, anterior hypothalamus, and
dorsolateral periaqueductal grey neurons. Interestingly, Ang II, angiotensinogen
and the primary receptors for Ang II, AT1R and AT2R, are widely expressed
in ventral mesencephalon, including the SNr in both primates and human
brain. However, if Ang II signaling takes place in SNr GABAergic cells and if it
can affect GABAergic neurotransmission in dopaminergic cells is not known.
Here we present evidence of Ang II signaling in GABAergic pars reticulata
projection neurons. We find that Ang II significantly decreases the frequency
of evoked firing of SNr projection neurons and increases the amplitude of
picrotoxin sensitive GABA(A) receptor mediated inhibitory post synaptic
currents (IPSC’s). These Ang II mediated effects were attenuated by Ang II
type 1 receptor (AT1-R) blocker, Losartan and were also blocked by a general
G-protein inhibitor, guanosine 5’-O-(2-thiodiphosphate) (GDP-β-s, 1 mM) in
the pipette solution, suggesting a G-protein dependent signaling mechanism in
these cells. These results provide, for the first time, evidence of Ang II-mediated
potentiation of GABA(A) receptors on SNr GABAergic projection neurons
and inhibition of their firing. Since GABAergic SNr projection neurons provide
most of the inhibitory input to dopaminergic neurons in the nigra compacta,
these data suggest that Ang II signaling in GABAergic cells could potentially
disinhibit dopaminergic neurons causing an imbalance between inhibitory and
excitatory tone which eventually results in increased dopaminergic cell firing.

W25. Rapid Reprogramming Method Differentiates

CuATSM Responders/Nonresponders From ALS Patient
Population
Cassandra Dennys-Rivers*, Xiaojin Zhang, Rochelle Rodrigo, Annalisa Hartlaub,
Joseph Beckman, Maria Clara Franco, Kathrin Meyer
Patient diversity and unknown disease cause are major challenges for drug
development and clinical trial design for ALS. Moreover, the heterogeneity of
the ALS patient population is not reflected in the currently available transgenic
animal models. Hence, the direct translation of potential therapeutics tested in
such models to the clinic has proven difficult. To address this issue, we utilized
a rapid reprogramming method to convert skin biopsies from ALS patients into
neuronal progenitor cells (NPC). Using induced astrocytes (iAs) differentiated
from these NPCs in co-culture with mouse embryonic motor neurons, we
have developed an in vitro model of ALS to screen potentially therapeutic
compounds. Using this assay, we have screened numerous compounds on
multiple sporadic (sALS) and familial (fALS) patient lines. Our data indicate
a diverse patient response to different therapeutic agents, suggesting shared
pathways of interest between patient subgroups. Here we investigated the

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 205
effects of one such compound, CuATSM, on iAstrocyte mediated motor neuron
toxicity in both sporadic and familial (mtSOD1 and C9ORF72 patients)
lines. We identified responders and nonresponders in co-culture assay for each
patient subpopulations. Next, we performed a detailed analysis of the effects
of CuATSM on known ALS disease markers (oxidative stress, mitochondrial
dysfunction, elevation of stress response systems). We identified one shared
parameter in mitochondrial activity present in all ALS patient CuATSM
responders, that was nonexistent in nonresponders. Treatment of iAstrocytes
with CuATSM restored this disease markeractivity to levels comparable to
healthy controls. Together, these findings suggest that patient iAstrocytes can
be used to identify both disease modifiers and pathways dysregulated in a given
individual. Shared pathways amongst patient responders implicated CuATSM
as a potential therapeutic strategy for additional disorders. These results
indicate that enhanced understanding of cellular profiles could aid clinicians in
determining the best treatment approach for patients in the future.

W26. Pipsqueak AI: A Standardized and Automated

Method of Biomarker Quantification in Digital Histology
Using Machine Learning
John Harkness*, Will O’Keefe, Grant Wade, Kristy Lawton, Allison Coffin, Barbara
Sorg
Quantification of immunofluorescent markers following confocal or
fluorescence microscopy often requires manual identification of cells or
biomarkers within images. This task is time intensive, difficult, and prone to
bias and errors. Unintentional bias and attentional limitations during analysis
can underlie poor reproducibility of findings in biomedical research and
represents a significant barrier to developing effective medical treatments,
and promoting confidence in scientific inquiry. We developed a “beta”
software package ([Link] designed to
improve automation and standardization of image analysis, called “Pipsqueak”
(Perineuronal net Intensity Program for the Standardization and Quantification
of Extracellular matrix Analysis Kit). Since its publication in 2016, Pipsqueak
beta has amassed approximately 1,800 users worldwide who use it to quantify
the intensity and number of perineuronal nets and other neural markers in
the brain. This technology significantly increases data reliability between
image raters and decreases the time required for analysis by more than 100-
fold. However, Pipsqueak beta requires high-contrast images in order to
automatically identify neurons. Suboptimal conditions, like high background
staining, off-target structures, overlapping or clustered biomarkers, and
atypical morphologies, can lead to artifacts and consequently to inaccurate
results and erroneous conclusions. Here, we used machine learning to tune a
U-NET convolutional neural network to accurately detect of three fluorescent

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biomarkers (Wisteria floribunda agglutinin, 8-oxo-dG, and parvalbumin) in
sections of rat prefrontal cortex. We demonstrate the potential to integrate
machine learning capabilities into our Pipsqueak technology to produce an
adaptive, high-throughput, biomedical image analysis platform that quickly and
accurately identifies biomarker targets. Furthermore, we were able to implement
“Pipsqueak AI” onto a touchscreen for direct interface with microscope
CMOS camera hardware. Our end goal is to advance the reliability and speed
of research findings and clinical diagnoses by making this technology widely
available to researchers and clinicians.

W27. A Cav2.3-Kv4.2 Complex Regulates A-Type Voltage

Gated K+ Currents in Hippocampal Neurons
Jonathan Murphy*, Lin Lin, Jakob Gutzmann, Jiahua Hu, Ron Petralia, Dax
Hoffman
The rapidly inactivating A-type outward K+ current mediated by Kv4.2
regulates action potential repolarization, subthreshold dendritic excitability, and
synaptic plasticity in CA1 pyramidal neurons of the hippocampus. The native
Kv4.2 channel complex includes auxiliary subunits Dipeptidyl aminopeptidase-
like proteins (DPP6) and the K+ channel interacting proteins (KChIPs1-4).
Recent evidence suggests that Kv4.2 function in hippocampal neurons is
regulated by R-type Ca2+ channel (Cav2.3) Ca2+ entry in a KChIP-dependent
manner. However, the molecular nature of this interaction has not been
explored. Here we present evidence for a Cav2.3-Kv4.2 binding interaction
that underlies Ca2+ regulation of Kv4.2. We first identified Cav2.3 and Kv4.2
as interaction partners in a mass spectrometry screen using Kv4.2 as bait and
confirmed the interaction by coimmunoprecipitation, immunofluorescence,
and electron microscopy in hippocampal neurons. Additionally, we found C/
YFP FRET between Cav2.3 and Kv4.2 and a reduced Kv4.2-GFP FRAP mobile
fraction in Cav2.3 knockout mouse neurons to provide further support for an
intimate Cav2.3-Kv4.2 interaction. To determine if Cav2.3 binding regulates
Kv4.2 function, we measured a Cav2.3-dependent increase in Kv4.2 current
(~25%) in the presence of the slow Ca2+ chelator EGTA, while the fast Ca2+
chelator BAPTA reversed this increase. Whole cell current recordings of A-type
current in Cav2.3 knockout neurons dendrites revealed a significant decrease
in current density (~45%) when compared to wild-type. Taken together, these
results support a Cav2.3-Kv4.2 interaction in which a CaV2.3 Ca2+ influx
regulates Kv4.2 function in CA1 hippocampal neurons. Ongoing research is
aimed at determining how dendrite function is shaped by the Cav2.3-Kv4.2
complex.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 207
W28. Lateral Hypothalamic Fast-Spiking Parvalbumin
Neurons Modulate Nociception Through Connections in
the Periaqueductal Gray Area
Justin Siemian*, Cara Borja, Sarah Sarsfield, Alexandre Kisner, Yeka Aponte
The lateral hypothalamus (LH) contains a diverse collection of cell types
crucial for orchestrating behaviors that facilitate survival. Over the past decade,
tremendous progress has been made on new methods that allow systematic
characterization of the function and connectivity of these heterogeneous
neuronal subtypes. While studies have begun to identify LH circuits that
regulate food intake and reward-related behaviors, less attention has been
given to the contributions of genetically-identified LH circuits that modulate
nociceptive behaviors. Here we examined how lateral hypothalamic neurons
that express the calcium-binding protein parvalbumin (PVALB; LH-PV
neurons), a small cluster of neurons within the LH glutamatergic circuitry,
regulate nociception in mice. Using optogenetics to modulate neuronal activity,
we found that photostimulation of LH-PV neurons suppressed nociception
to an acute, noxious thermal stimulus, whereas photoinhibition potentiated
thermal nociception. Moreover, brain slice electrophysiology recordings using
channelrhodopsin (ChR2)-assisted circuit mapping (CRACM) revealed
that LH-PV axons form functional excitatory synapses on neurons in the
ventrolateral periaqueductal gray (vlPAG). Furthermore, photostimulation
of LH-PV axons in the vlPAG suppressed nociception to both thermal and
chemical visceral stimuli. Interestingly, antagonism of mu-opioid receptors
or CB1 cannabinoid receptors with systemically-administered naltrexone
or rimonabant, respectively, did not abolish the antinociception evoked
by activation of this LH-PV to vlPAG pathway. Importantly, none of the
optogenetic manipulations significantly affected locomotor activity or anxiety-
like behavior as measured by the open-field and elevated plus maze tests,
suggesting that the role of LH-PV neurons is likely specific to nociception.
Similar to our results for these acute pain tests, photostimulation of LH-PV
neurons or their axonal projections in the vlPAG also significantly attenuated
thermal and mechanical hypersensitivity induced by a model of chronic
inflammatory pain. Together, these results directly implicate LH-PV neurons
in modulating nociception, thus expanding the repertoire of survival behaviors
regulated by LH circuits.

208 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

W29. Gut–Brain Modulation of Central Thirst Circuitry
Controls Satiation
Chris Zimmerman*, Erica Huey, Jamie Ahn, Lisa Beutler, Chan Lek Tan, Seher
Kosar, Ling Bai, Yiming Chen, Timothy Corpuz, Linda Madisen, Hongkui Zeng,
Zachary Knight
Satiation is the process by which eating and drinking reduce appetite. For thirst,
oropharyngeal cues have a critical role in driving satiation by reporting to the
brain the volume of fluid that has been ingested. By contrast, the mechanisms
that relay the osmolarity of ingested fluids remain poorly understood. Here we
show that the water and salt content of the gastrointestinal tract are precisely
measured and then rapidly communicated to the brain to control drinking
behaviour in mice. We demonstrate that this osmosensory signal is necessary
and sufficient for satiation during normal drinking, involves the vagus nerve
and is transmitted to key forebrain neurons that control thirst and vasopressin
secretion. Using microendoscopic imaging, we show that individual neurons
compute homeostatic need by integrating this gastrointestinal osmosensory
information with oropharyngeal and blood-borne signals. These findings reveal
how the fluid homeostasis system monitors the osmolarity of ingested fluids to
dynamically control drinking behaviour.

W30. The Mechanisms and Functional Consequences of

Interhemispheric Plasticity
Emily Petrus*, Alan Koretsky
The ability of the brain to re-organize after amputation or nerve damage
mediates recovery. Beneficial adaptations are required to compensate for injury,
but maladaptive phenotypes such as phantom limb pain or hyperalgesia can
also occur. A hallmark of unilateral loss of sensation in adults is the bilateral
recruitment of primary and secondary somatomotor brain regions responding
to sensation in the unaffected limb. The unaffected limb can cause activation
of the affected limbs’ cortical areas. The cellular mechanisms underlying these
changes and whether they are adaptive or maladaptive for recovery are not
understood.
We have developed an adult mouse model of peripheral denervation by
transecting the nerve bundle connecting the whiskers to the brain. These mice
mimic clinical phenotypes observed by functional magnetic resonance imaging
(fMRI). This perturbation yields dramatic changes in cortical circuitry in
primary somatosensory barrel cortex (S1BC). The deprived S1BC is recruited
to respond to intact whisker stimulation by strengthening callosal synapses
specifically from intact S1BC to layer 5 (L5) principal neurons in deprived
S1BC. These neurons are hyperexcitable and have an increase in glutamatergic
receptor function.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 209
To determine if additional somatosensory processing areas are also affected by
denervation, cells were labeled with retrograde viral tracers and pre- and post-
synaptic responses and intrinsic properties in neurons were recorded. Deprived
S1BC neurons connected to pain regions such as the anterior cingulate cortex
(ACC), or somatomotor areas such as secondary somatosensory cortex (S2)
or motor cortex (M1) undergo unique modifications depending on the area to
which they project. These changes indicate that there has been a shift in the state
of deprived S1BC towards responsiveness to intact whisker stimulation. The
output-specific targeting of the callosum should guide the study of behavioral
adaptations after these sensory perturbations.

W31. LTD Requires Engagement of Two Distinct

Mechanisms for Suppression of CaMKII Synaptic
Targeting
Sarah Cook*, Ulli Bayer
Learning, memory, and cognition are mediated by hippocampal long-term
potentiation (LTP) and depression (LTD) of synaptic strength. These
bi-directional processes require the Ca2+/calmodulin (CaM)-dependent
protein kinase II α isoform (CaMKIIα) and its auto-phosphorylation at
T286. However, only LTP requires accumulation of CaMKII at dendritic
spine-localized excitatory synapses, mediated by binding to synaptic
NMDA receptors (NMDARs). During LTD, CaMKII instead targets shaft-
localized inhibitory synapses and contributes to inhibitory potentiation. Still,
mechanisms regulating this input-specific, bi-directional synaptic targeting of
CaMKII remain largely unknown. Here, we explore this differential CaMKII
synaptic targeting and find that LTD requires suppression of CaMKII
accumulation at excitatory synapses by coincidental engagement of two
distinct mechanisms: the death associated protein kinase 1 (DAPK1) and
CaMKII T305/306 autophosphorylation (pT305/306). Our lab has previously
demonstrated that DAPK1 mediates LTD by making CaMKII/NMDAR
binding LTP-specific. We have also shown that T305/306 phosphorylation
prevents CaMKII/NMDAR binding, at least in vitro. Thus, we endeavored to
examine how these mechanisms regulate CaMKII synaptic targeting during
LTD. To study the regulation of CaMKIIa movement during plasticity, we used
FingR intrabodies to simultaneously live-image endogenous CaMKIIa and
excitatory and inhibitory synapse markers in WT and mutant mouse neurons.
Either DAPK1 knockout (KO) or overexpression of a phospho-null mutation
of CaMKII T305/306 (T305/6AA) was sufficient to allow accumulation of
CaMKII at excitatory synapses during both LTP and LTD. By contrast, only
phospho-null T305/6AA, but not DAPK1 KO, was sufficient to suppress
LTD-induced CaMKII accumulation at inhibitory synapses. Furthermore,
we demonstrate for the first time that T305/306 phosphorylation is indeed

210 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

(i) induced by LTDstimuli and (ii) required for normal LTD (but not LTP).
Thus, DAPK1 and T305/306 auto-phosphorylation control the LTP vs. LTD
bi-directional synaptic targeting of CaMKII.

W32. Biased Modulation of a Ligand-Gated Ion Channel

Riley Perszyk*, Sharon Swanger, Chris Shelley, Alpa Khatri, Gabriela Fernandez-
Cuervo, Matthew Epplin, Pernille Bülow, Ethel Garnier-Amblard, Pavan
Gangireddy, Gary Bassell, Hongjie Yuan, David Menaldino, Dennis Liotta, Lanny
Liebeskind, Stephen Traynelis
Allosteric modulators of ion channels typically alter the transitions rates
between conformational states without changing the properties of the open
pore. We describe identification of a novel class of positive allosteric modulators
of N-methyl D-aspartate receptors (NMDARs) that mediate a calcium-
permeable component of glutamatergic synaptic transmission and play essential
roles in learning, memory, cognition, as well as neurological disease. EU1622-
14 increases agonist potency and channel open probability, slows receptor
deactivation, in addition to decreasing both single channel conductance
and calcium permeability. The unique functional selectivity of this chemical
probe reveals a mechanism for enhancing NMDAR function while limiting
excess calcium influx, and shows that allosteric modulators can act as biased
modulators of ion channel permeation.

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 211
 Presenter Disclosures
Albers, Gregory: Frankel, Wayne:
iSchemaView: Stock / Equity, Board Praxis Precision Medicines: Consultant
Member, Consultant (Self). Genentech: (Self).
Advisory Board (Self).
Frye, Richard:
Anagnostou, Evdokia: Cox Biosciences: Advisory Board (Self).
ROCHE: Consultant (Self). Quadrant: Iliad Neurosciences: Advisory Board
Consultant (Self). (Self). NeuroNeeds: Advisory Board
(Self). Finch Therapeutics: Consultant
Arroyo, Netz: (Self).
University of California: Royalties (Self).
Geschwind, Dan:
Bayer, Ulli: Roche: Contracted Research (Self).
Neurexus Therapeutics, LLC: Board Takeda: Consultant (Self). Axial
Member (Self). University of Colorado: Biotherapeutics: Advisory Board (Self).
Patent (Self). Acurastem: Advisory Board (Self).
Beniczky, Sándor: Falcon Computing: Advisory Board
Brain Sentinel: Consultant (Self). (Self).
Epihunter: Consultant (Self). Geyer, Mark:
Bleck, Thomas: San Diego Instruments: Stock / Equity
Ceribell Corporation: Consultant (Self). (Self).
SAGE Corporation: Consultant (Self). Hill, Matthew:
Bonn-Miller, Marcel: Sophren: Advisory Board (Self).
Canopy Growth Corporation: Employee Holly, Elizabeth:
(Self). AusCann: Board Member (Self). Nia Therapeutics: Employee, Stock /
Zynerba Pharmaceuticals: Employee Equity, Board Member (Spouse).
(Self). Tilray: Consultant (Self).
Huddleston, Daniel:
Bredt, David: PTC Therapeutics: Advisory Board
Johnson and Johnson: Employee (Self). (Self). Lightbox Science: Stock / Equity
Cashman, Neil: (Self).
ProMIS Neurosciences: Stock / Equity, Kearney, Jennifer:
Contracted Research, Board Member Encoded Genomics: Consultant,
(Self). Royalties (Self). Life Splice Pharma:
Devilbiss, David: Royalties (Self). Stoke Therapeutics:
Cerora: Stock / Equity (Self). Royalties (Self). Xenon Pharmaceuticals:
Royalties (Self). GW Pharma: Royalties
Dreyer, Jakob: (Self). NeuroCycle: Royalties (Self).
H. Lundbeck A/S: Employee (Self). Praxis Precision Medicines: Contracted
Eriksen, Jason: Research (Self). Ovid Therapeutics:
Alzeca, Inc.: Board Member (Self). Contracted Research (Self).
Teomics, LLC.: Board Member (Self).

212 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Lichtman, Aron: Snyder, Gretchen:
I received a payout on stocks from Intra-Cellular Therapies Inc: Employee,
Lundbeck when they acquired Abide Stock / Equity (Self).
Therapeutics: Advisory Board (Self).
Sea Pharmaceuticals has given me stocks, Sombers, Leslie:
which will have value if they go public: Pine Research Instruments: Employee
Advisory Board (Self). Corbus I gave a (Spouse). Pinnacle Technology, Inc:
seminar and met with the copy this past Contracted Research (Self).
year: Honoraria (Self). Stacpoole, Sybil:
Lovinger, David: Teva pharmaceuticals: Honoraria (Self).
Elsevier Incorporated: Honoraria (Self). Steward, Oswald:
Malhotra, Anil: Axonis Inc: Stock / Equity (Self).
Genomind, Inc.: Consultant (Self). Tappan, Susan:
Margolis, Elyssa: MBF Bioscience: Employee (Self).
BlackThorn Therapeutics: Contracted Traynelis, Stephen:
Research (Self). NeurOp Inc: Stock / Equity (Self).
Napadow, Vitaly: Janssen: Consultant, Contracted
Cala Health, Inc.: Consultant (Self). Research (Self). Emory: Royalties, Patent
(Self). Sage Therapeutics: Advisory
Phillips, Paul: Board (Self). Allergan: Contracted
Numedii, Inc: Employee (Spouse). Research (Self).
Plaxco, Kevin: Tunbridge, Elizabeth:
Diagnostic Biochips: Advisory Board Unrestricted Educational Grant
(Self). Eccrine Systems, Inc: Advisory Recipient: Contracted Research (Self).
Board (Self). Thermofischer: Consultant
(Self). Vandrey, Ryan:
Canopy Health Innovations: Consultant
Sandoval, Darleen: (Self). Brain Solutions Inc: Advisory
Novo Nordisk: Contracted Research Board (Self). FSD Pharma: Advisory
(Self). Medimmune: Contracted Board (Self). Zynerba Pharmaceuticals:
Research (Self). Consultant (Self).
Scida, Karen: Yasuda, Ryohei:
Employment: Stock / Equity (Self). Florida Lifetime Imaging LLC: Stock /
Equity (Self).
Skolnick, Phil:
Opiant Pharmaceuticals: Employee
(Self).

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 213
The following Cai, Denise Fadok, Jonathan
presenters had Calipari, Erin Fakler, Bernd
nothing to disclose Campbell, Rianne Farero, Ryan
Achterberg, Marijke Cang, Jianhua Fenno, Lief
Adhikari, Avishek Carter, Matt Ferland, Jacqueline-Marie
Adhikary, Sweta Chartoff, Elena Ferrario, Carrie
Aizenman, Elias Chen, Hsiao-Huei Ferris, Mark
Alhadeff, Amber Choquet, Daniel Fetterly, Tracy
Alonso-Caraballo, Yanaira Cisneros, Irma Finan, Patrick
Amaya, Kenneth Clancy, Kathryn Ford, Chris
Anastasio, Noelle Coffey, Eleanor Foussias, George
Anderson, Anne Cohen, Akiva Fowler, Christie
Anderson, Eden Collins, Anne Fox, Megan
Andrieux, Annie Contet, Candice Fragale, Jennifer
Argyelan, Miklos Conti, Alana Frank, Michael
Baca, Serapio Contractor, Anis Frantz, Kyle
Bains, Jaideep Cooke, Bradley Fricker, Lloyd
Bangasser, Debra Cope, Zackary Friend, Samantha
Banks, Matthew Corbit, Laura Fujikawa, Denson
Bao, Shaowen Cosgrove, Kelly Fyffe, Robert
Barr, Cathy Coutellier, Laurence Gallitano, Amelia
Barson, Jessica Covey, Daniel Gardner, Eliot
Bateup, Helen Dagher, Alain Giannotti, Giuseppe
Beauchamp, Michael Dalva, Matthew Giardino, William
Becker, Jill Darcq, Emmanuel Goldberg, Lisa
Behrens, Margarita Dell’Acqua, Mark Golden, Sam
Benamar, Khalid Devi, Lakshmi Gray, John
Berke, Joshua de Wit, Harriet Greger, Ingo
Best, Kaitlin Diaz, Elva Greif, Karen
Birdsong, William Diba, Kamran Gremel, Christina
Bizon, Jennifer Diehl, Maria Griffin, Amy
Blain-Moraes, Stefanie Dong, Chunyang Grueter, Brad
Blendy, Julie Duncan, Dominique Guha, Suman
Bolduc, Francois Ebner, Natalie Guindon, Josee
Boos, Terrence Edwards, Robert Gundersen, Brigitta
Borgland, Stephanie Ellman, Lauren Haass-Koffler, Carolina
Born, Heather Engin, Elif Halbout, Briac
Bortz, David Erhardt, Sophie Hall, Edward
Buonanno, Andres Faas, Guido Halladay, Lindsay

214 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

Han, Sung Kanold, Patrick Mather, Mara
Haney, Margaret Kantarci, Kejal Mathur, Brian
Hansen, Kasper Karkhanis, Anushree Matikainen-Ankney,
Hardwick, J. Marie Kesner, Andrew Bridget
Harris, Kristen Khokhar, Jibran Matsui, Aya
Harris-Warrick, Ronald Kippin, Tod Maurer, Andrew
Hart, Evan Kirschner, Matthias McCarren, Hilary
He, Jenny Kirson, Dean McCullumsmith, Robert
Hearing, Matthew Knackstedt, Lori McCurdy, Christopher
Hell, Johannes Knight, Zachary McDannald, Michael
Henn, Fritz Knowles, James McElligott, Zoe
Hentges, Shane Koob, George McGinty, Jacqueline
Herman, Melissa Kuhlman, Sandra McGovern, Dillon
Hermes, Dora Kutlu, Munir McLaughlin, Ryan
Hesselgrave, Natalie Lee, Hey-Kyoung McMahon, Lance
Hohmann, Andrea Lee, Hye Young McRae-Clark, Aimee
Hollon, Nick Leibowitz, Sarah McReynolds, Jayme
Homanics, Gregg Lemos, Julia Miller, Courtney
Honeycutt, Jennifer Lenkei, Zsolt Miller, Kai
Hope, Bruce Lepage, Jean-Francois Mingote, Susana
Howard, Christopher Li, Bo Miranda-Barrientos, Jorge
Howe, Mark Lippe, Sarah Misic, Bratislav
Hu, Xiaoping P. Lopez, Alberto Moaddab, Mahsa
Hudetz, Anthony Loweth, Jessica Morales, Marisela
Hyde, Thomas Lu, Hui-Chen Morgan, Daniel
Iakoucheva, Lilia Lu, Wei Morgan, Michael
Izquierdo, Alicia Lucas, Elizabeth Morrow, Jonathan
Jacob, Tija Lupica, Carl Murphy, Anne
Jacobs, David Madangopal, Rajtarun Nakagawa, Terunaga
James, Morgan Magnotti, John Nautiyal, Katherine
Janda, Kim Maher, Brady Nelson, Alexandra
Jensen, Patricia Malvaez, Melissa Newman, Amy
Johansen, Joshua Manvich, Daniel Niell, Cristopher
Johnson, Amy Maren, Stephen Nolan, Amber
Jonas, Elizabeth Maricq, Andres Nunes, Eric
K. Namboodiri, Vijay Markovic, Tamara O’Connor, Richard
Mohan Martin, David Oeltzschner, Georg
Kaczmarek, Leonard Marvin, Jonathan Olsen, Christopher
Kallupi, Marsida Massaly, Nicolas Olsen, Michelle

JAN. 25–30, 2020 • BIG SKY RESORT, BIG SKY, MONTANA 215
Orsini, Caitlin Rumbaugh, Gavin Varela, Carmen
Otis, James Saddoris, Michael Veenema, Alexa
Padilla, Stephanie Sartorius, Alexander Venniro, Marco
Park, Kevin Schmeichel, Brooke Vieira, Philip
Paukert, Martin Schmidt, Heath Voineskos, Daphne
Paulson, Olaf Schnupp, Jan Voon, Valerie
Pennington, David Schulien, Anthony Wanat, Matthew
Petzschner, Frederike Schwendt, Marek Wassum, Kate
Pierce, Chris Schwieler, Lilly Wasterlain, Claude
Pinborg, Lars H. Segarra, Annabell Waung, Maggie
Pitts, Elizabeth Sehgal, Megha Weerts, Elise
Pletnikov, Mikhail Selvan, Vani Weil, Zachary
Plude, Dana Sharma, Abhisheak Wenzel, Jennifer
Porrino, Linda Sharpe, Melissa West, Anne
Pradhan, Amynah Sheahan, Tayler Wetsel, William
Preller, Katrin Shepherd, Jason Whitaker, Leslie
Priebe, Nicholas Siciliano, Cody Wilfong, Angus
Radke, Anna Slocum, Samuel Wilkerson, Jenny
Radley, Jason Smit, August Williams, Kevin
Rainville, Jennifer Smith, Alexander Willis, Ian
Ram, Madabhushi Smith, Katharine Winstanley, Catharine
Rangel, Lara Smith, Stephen Wu, Long-Jun
Rau, Andrew Spijker, Sabine Xi, Zheng-Xiong
Recanzone, Gregg Spreng, Nathan Yang, Yongjie
Reichelt, Amy Stefanik, Michael Yohn, Samantha
Reiner, David Stern-Bach, Yael Young, Jared
Reyes, Beverly Swanson, Geoffrey Yue, Zhenyu
Risbrough, Victoria Sweet, Robert Zelikowsky, Moriel
Roche, Katherine Tadross, Michael Zell, Vivien
Rodriguez-Romaguera, Tamkun, Michael Zhang, Li
Jose Tanner, Bradley Zheng, Binhai
Root, David Tao, Huizhong Zlebnik, Natalie
Rosen, Merri Tasker, Jeffrey Zukin, R. Suzanne
Rothschild, Gideon Tejeda, Hugo Zuo, Yi
Rothwell, Patrick Torregrossa, Mary Zych, Sarah
Royer, Sebastien Trudeau, Louis-Eric
Rozeske, Robert Van Meter, Anna

216 53 RD ANNUAL WINTER CONFERENCE ON BRAIN RESEARCH

SAVE THE DATE

2021
WINTER CONFERENCE
ON BRAIN RESEARCH

SNOWBIRD, UTAH
JANUARY 23-28, 2021