The Biology of Memory

How do we remember?
 Learning/Memory
• An evolutionary adaptation to a nonstatic
environment
– Adaptation to changing conditions

• A relatively permanent change in behavior as

a result of a specific prior experience
 Donald Hebb
Hebb (1949) Organization
of Behavior
“father” of behavioral
neuroscience
Learning/memory can (and
should!) be studied as
biological processes
 Karl Lashley (1890-1958)
IN SEARCH OF THE ENGRAM
Engram: The physical representation of a
memory in the brain; hypothetical construct.

Where is memory located?

Lashley’s hypothesis: The engram is located in the
cerebral cortex
If you know where it is, then you can take it out.
Can you find the
cheese without your
cortex?
Lashley’s Search for the Engram
Where is it?
 Lashley’s Conclusions

• Memory is stored diffusely in the brain

• There is no localizable engram

• All parts of the cortex play an equal role in memory

storage
• Two important things occurred in the early
1970’s to change memory research

– Brenda Milner’s summary of work with Patient

H.M.
– The discovery of Long-Term Potentiation (LTP) in
the hippocampus
 Thoughts about memory in the 1970’s

• Memory can be studies at the biological level (Hebb’s

proposition)
• Memories are not localized in a specific area of the brain
[cortex] (Lashley)
Patient H.M. has contributed
more to the study of the
biological basis of memory than
anyone else in the history of
psychological research
 Patient H.M.

• H.M. suffered severe epilepsy since age 16

– had to quit school
– couldn’t get a job
– couldn’t ride his bike
– couldn’t play with his friends
– couldn’t have a girlfriend, or do anything that normal 16-year-olds do
• Etiology of epilepsy (suspected):
– At age 9 he was in a bicycle accident and was unconscious for 5
minutes; mild seizures began at age 10; severe at age 16.
 Patient H.M.

• Seizures:
– Severe (grand mal) seizures (1 per week)
– Mild (petit mal) seizures often (about every 10 minutes)
– Constant state of confusion and stupor

• Unresponsive to anticonvulsant medications, even at near-

lethal doses
• 1953 (H.M. was 27 years old)
– EEG showed no clear locus of epilepsy, but confirmed bilateral,
involved structures in the medial temporal lobe (sub-cortical regions)
 H.M.’s Radical Surgery

Bilateral temporal lobectomy

– August 25, 1953
– removed medial temporal lobes in both hemispheres
– areas removed were most of the hippocampus and parts
of the amygdala, some overlying cortex
– surgery performed before in patients, with no significant
side effects
H.M.
Bilateral medial
temporal
lobectomy

Removed 8-cm
extent of
hippocampus
 The Surgery Was A Success!

• Epileptic seizures became much more mild

• Seizures were controllable with medication

• BUT……..
Severe memory problems were soon
discovered
Introduction of H.M.

Scoville & Milner

(1957)
Scoville Milner
“After operation, this young man could no longer recognize the hospital staff nor
find his way to the bathroom, and he seemed to recall nothing of the day-to-day
events of his hospital life…

Ten months ago the family moved from their old house to a new one a few blocks
away on the same street; he still has not learned the new address, though
remembering the old one perfectly, nor can he be trusted to find his way home
alone…

“His mother also states that he will do the same jigsaw puzzles day after day
without showing any practice effect and that he will read the same magazines
over and over again without finding their contents familiar…

“This patient has even eaten lunch in front of one of us (B.M.) without being able
to name, a mere half hour later, a single item of food he had eaten; in fact, he
could not remember having eaten lunch at all.”

Scoville & Milner (1957)

 Memory Deficits

1. H.M. had slight retrograde amnesia

2. H.M. had severe anterograde amnesia

 AMNESIA

• Retrograde Amnesia: Inability to remember events

that occurred prior to the brain trauma.
– H.M. couldn’t recall events that occurred 1-2 years prior to
the surgery

• Anterograde amnesia: Inability to remember events

that occurred after the brain trauma.
– H.M. appeared unable to form new memories!
 H.M. Couldn’t Remember...

• What he had eaten for lunch

• Indeed, whether he had eaten lunch or not!
• The name of his neurosurgeon or nurses
• What color socks he was wearing (unless he looked!)
• If he had read a certain magazine article before
• Couldn’t remember beginning of story half-way through
• Where he was
• The location of his new house
• That he had just had brain surgery!
 Tests Used To Assess H.M.’s Memory

• Short-term memory: seemed relatively normal

remember a list of digits

remember a list of common items

remember the name of the person in the room

 Tests Used To Assess H.M.’s Memory

But ……

if he was distracted for even a few minutes, no

memory for the items at all!
What Does H.M.’s Case Tell Us About Memory?

• Strengthened theoretical distinction between

short-term and long-term memory

– H.M. had short-term memory, but seemed unable to make

long-term memories
– Consolidation was affected
What Does H.M.’s Case Tell Us About Memory?

But… not all memories were affected!

 Tasks that Further Defined
H.M.’s Memory

1) Mirror drawing task:

 February 10,
1999
Good morning,
Today is Wacky Day!
I hope you have fun! …
 Tasks that Further Defined
H.M.’s Memory

2) Tower of Hanoi:
 Tower of Hanoi

Goal: to move all disks

from one peg to
another

Rules:
1. Move only one disk at
a time
2. Cannot place a larger
disk on top of a
smaller disk

[Link]
 Tasks that Further Defined
H.M.’s Memory

3) Rotary pursuit:
 Tests Used To Assess H.M.’s Memory

• Outcomes of these types of tasks

– H.M. performed the tasks perfectly after he had learned them

– H.M. didn’t remember ever having seen the tasks, or performing
the tasks, before!

– He remembered how to do them, but didn’t remember ever

experiencing them before.
 What Does H.M.’s Case Tell Us About
Memory?

“the first time an amnesic patient claimed to have no memory for a

previous experience, while demonstrating that memories had been
formed”
 What Does H.M.’s Case Tell Us About
Memory?
Two memory systems:

1. declarative = memories for facts, events, dates, faces; have

you ever seen this task before? Explicit memory: conscious
recollection

2. procedural = memories for procedures or skills, how to do

something; can you perform this task? Implicit memory:
unconscious performance
Declarative Memory and
the Hippocampus
Hippocampus – region most
affected by surgery
 What Does H.M.’s Case Tell Us About
Memory?
Ability to exhibit short-term but not long-term
memories implies a deficit in the consolidation
process
– there is a process of consolidation
– the hippocampus is involved in the consolidation of
long-term declarative memories
 What Does H.M.’s Case Tell Us About
Memory?
• Consolidation takes place over a long period of time
– retrograde amnesia for 1-2 years prior to surgery
– suggests a 1-2 year consolidation period!

• Declarative memories are not permanently stored in the

hippocampus (H.M. has perfect retention of early memories)

• The hippocampus is needed to transfer memories to some

other (unknown) location (cortex?)
 H.M. = Henry Gustav Molaison

• H.M. died of respiratory failure on

Dec 2, 2008 at 5:05pm, at his nursing
home in Windsor Locks, Conn.
• He was 82 years old, he left no
survivors

• Research continued for 55 years (and

is still continuing)!
• He will always be one of the most
significant contributors to the
scientific study of memory
Dec 2, 2009

Jacopo Annese, UCSD

 Where are we today?

• The medial temporal lobe is important for some

types of memory

• Especially the hippocampus

- declarative (not procedural) memories

- consolidation of memory to long-term
- long-term declarative memories do not reside in
the hippocampus
A 5-minute summary of H.M. and his contributions to memory research

[Link]
 Other Types of Amnesia:
Alzheimers Disease and
Wernicke-Korsakoff Syndrome
 Other types of amnesia
• Alzheimer’s disease
 Alzheimer’s Disease
• Onset typically after age 65
– Early onset before 65
• 3 million people over age 65 in U.S. are
afflicted
– 5% of population 75-84 years
– 50% of population over 85 years
• Definitive diagnosis at autopsy
 Alzheimer’s Disease
• Genetic?
– Down’s syndrome
– Trisomy 21 (3 copies of chromosome 21)
– If live past age 30, most develop Alzheimer’s

• Chromosomes 21, 14, 1, and 19 all linked to

Alzheimer’s
 Alzheimer’s Disease
• Dementia (general cognitive – Language impairments
decline)
– Spatial abilities affected
– Memory loss**
– Decline in social functioning
– Confusion*
– Loss in brain volume
– Depression
• 10-15% of frontal cortex
– Hallucinations
– Delusions
– Disturbances in eating
– Disturbances of sleep
 Brain abnormalities in
Alzheimers Disease
• Loss of ACh (hippocampus and frontal cortex)
• Plaques
• Tangles
 Alzheimer’s Disease
• Memory impairments
– Linked to loss of ACh to hippocampus
– Declarative memories affected (initially)
• Spatial, names of familiar people, events
 Alzheimer’s Disease
• Memory impairments linked
to loss of ACh

• Loss of ACh neurons in

nucleus basalis
– Up to 90% loss
• ACh antagonists
(scopolamine) interfere
with memory
– act at muscarinic receptors
in hippocampus
 Alzheimer’s Disease
• Plaques and tangles
• Cortex
 Alzheimer’s Disease
• Plaques – amyloid deposits
– Amyloid precursor protein ----
> Aβ40
• 40 amino acid subunits

– Alzheimer’s: Aβ42
• 42 amino acid subunits
• Deposits in/near cells; toxic
 Alzheimer’s Disease
• Tangles –
– Accumulation of tau
protein (microtubule-
associated protein)
– Alzheimer’s: tau
detaches
• Axons cannot function
• Affects neuronal
communication
 Tau
• Tau is one of the microtubule associated
proteins (MAPs). Tau found in axons
– MAP2 is found in dendrites – serves similar
function
• There are other MAPs but tau and MAP2 are
the most abundant in the nervous system
 Alzheimer’s Disease
• Treatments
Acetylcholinesterase (AChE) inhibitors
• Physostigmine (Synapton)
• Rivastigmine (Exelon patch)
ACh
• Tacrine (Cognex)
• Donepezil HCl (Aricept) AChE

choline + acetate
 Alzheimer’s Disease
• Treatments
– Estrogen-replacement therapy
• Women have higher incidence of Alz than men
• Estrogen loss at menopause
• Estrogen-replacement reduces risk of Alz
– Also decreases heart disease and osteoporosis
– Increases risk of breast cancer
 Alzheimer’s Disease
• Marijuana may be the most effective!

– Δ9-THC (active ingredient)

– prevents ACh breakdown more effectively than traditional AChE

inhibitors

– Marijuana also used medically for treatment of: glaucoma, nausea in

chemotherapy and AIDS patients
 Declarative memory
• Semantic – general knowledge; facts about
the world
• Episodic – memory for personal experiences
that occur at a particular time and place

• Early Alzheimer’s disease – episodic impaired

more dramatically; impaired sooner than
semantic
Wernicke-Korsakoff Syndrome
 Wernicke-Korsakoff Syndrome
• Seen in chronic
alcoholics
• Not due to alcohol
– Thiamine deficiency
(vitamin B1)

• Degeneration of
mammillary bodies
– Part of hypothalamus
– Provide input to
hippocampus
 Wernicke-Korsakoff Syndrome
• Wernicke’s encephalopathy
– Ocular disturbances
– Changes in mental state (i.e. confusion)
– Unsteady stance and gait

• Korsakoff’s syndrome
– Severe anterograde amnesia (declarative affected more than procedural)
– Variable presentation of retrograde amnesia
– Deficits in language, executive function
The Hippocampus and
Spatial Memory
Hippocampus and Spatial memory
Hippocampus and Spatial memory

– Animals (including humans) don’t just learn a

series of turns
• Relative spatial arrangement of objects
– Cognitive map
– Orientation in space
– Maze learning
 Morris Water Maze

Animals must find location of

hidden platform (submerged
below water line)

Learn where platform is by

using extra-maze cues

Hippocampal lesions disrupt

performance
 Morris Water Maze

Before learning Test performance

 Water maze performance by rats
Left: hippocampal lesion Right: control
 Hippocampal place cells
ED
R
• Specific cells, active when animal is in a particular

E
location

V
– Or moving toward a specific place

O
• Head direction cells

C
– Active when head is oriented toward a location

OT
Birds that store (cache) food have larger hippocampus than non-food
storing birds

N
• London cab drivers have larger hippocampus than the general population
 Spatial Memory and Alzheimer’s Disease
ALZ NORMAL

COPY

IMM RECALL
 The First Engram:
Eyeblink Conditioning
 Richard Thompson
HE FOUND THE FIRST ENGRAM!
The Cerebellum
Eyeblink Conditioning:

Conditioned stimulus (CS) – neutral, e.g. tone

Unconditioned stimulus (US) – puff of air

Conditioned response (CR) eyeblink in presence of

CS, before the US is given
 EYEBLINK CONDITIONING
IN HUMAN INFANTS

Tone CS + Airpuff US

Airpuff (US) elicits an

eyeblink (UR)

Eventually, Tone CS elicits

an eyeblink (CR)

Photo courtesy of Dr. Dragana Claflin

EYEBLINK CONDITIONING
• Requires the cerebellum
• Engram (memory trace) in the
lateral interpositus nucleus
• LIN receives information about
the CS (tone) and the US
(air puff)

CS (tone)

US (air puff)
 Cerebellar damage
ED
ER
• Eyeblink response is specific to the eye being
trained (the eye receiving the air puff)

V
other eye doesn’t blink!

O
T
only)
C
• Unilateral damage to cerebellum (one side

N O
– Impairs eyeblink conditioning only on that side
– Can learn the eyeblink response on the other side
Two Kinds of Eyeblink Conditioning

CS (tone) Delay
US (air puff) (cerebellum)

No stimulus (memory?)

CS (tone) Trace
(cerebellum + hippocampus)
US (air puff)

Time
 Eyeblink Conditioning in Humans
• Diana Woodruff-Pak
(Temple University)
– Normal aging
– Alzheimer’s Disease
– H.M.
Trace Eyeblink in Alzheimer’s
• Two important things occurred in the early
1970’s to change memory research

– Brenda Milner’s summary of work with Patient

H.M.
– The discovery of Long-Term Potentiation (LTP) in
the hippocampus
Cellular Mechanisms of Learning
 Hebbian Synapse
Hebb (1949) Organization of Behavior
“father” of behavioral neuroscience

A synapse that increases its effectiveness

because of simultaneous activity in
pre- and post-synaptic neurons
 Long-Term Potentiation (LTP)
• Bliss and Lømo (1973)

• One of the greatest discoveries ever made

• Hippocampal slices (in vitro)

– in vitro: “in glass;” in an artificial environment
(petri dish)
– in vivo: “in a living organism”

• Form of synaptic plasticity

 Long-Term Potentiation (LTP)
• Learning/Memory: A relatively permanent
change in behavior as a result of a specific
prior experience

• LTP: A long lasting (days or weeks) change in

the activity of a cell as a result of presynaptic
tetanic stimulation
 Long-Term Potentiation (LTP)
• Learning/Memory: A relatively permanent
change in behavior as a result of a specific
prior experience

• LTP: A long lasting (days or weeks) change in

the activity of a cell as a result of presynaptic
tetanic stimulation
 Long-Term Potentiation (LTP)
• Learning/Memory: A relatively permanent
change in behavior as a result of a specific
prior experience

• LTP: A long lasting (days or weeks) change in

the activity of a cell as a result of presynaptic
tetanic stimulation
 Tri-synaptic Circuit

Synapse #1:
Dentate gyrus
Synapse #2: area
CA3
Synapse #3: area
CA1

hippocampus also called Ammons Horn; CA = Comu Ammonis

 Tri-synaptic Circuit

Perforant path sends

axons to dentate
gyrus

Dentate gyrus sends

axons to area CA3

CA3 neurons send

axons (known as
Schaffer collaterals
to area CA1
(synapse on
pyramidal neurons
hippocampus also called Ammons Horn; CA = Comu Ammonis
 LTP
• Pyramidal neurons in area CA1 exhibit
experience-dependent changes in activity

• Pyramidal neurons get input from Schaffer

collaterals
– Stimulate Schaffer collaterals

– Record activity of pyramidal neurons

• Graded potentials in pyramidal neurons
Stimulate A:
Schaffer collaterals

Record from B:
pyramidal neurons
 Procedure for LTP
• Record from inside pyramidal neurons
• Baseline: Stimulate Schaffer collaterals with weak stimulus
(record pyramidal cell response)
• Tetanic stimulation of Schaffer collaterals (experience)
– High frequency stimulation (theta activity)
• Test: present original weak stimulus to Schaffer collaterals
(record pyramidal cell response)
Molecular Mechanisms
of LTP
Different Types of Glutamate Receptors
 Tri-synaptic Circuit

Perforant path sends

axons to dentate
gyrus

Dentate gyrus sends

axons to area CA3

CA3 neurons send

axons (known as
Schaffer collaterals
to area CA1
(synapse on
pyramidal neurons
hippocampus also called Ammons Horn; CA = Comu Ammonis
LTP
 Glutamate Receptors
• NMDA: N-methyl-D-aspartate

• AMPA: α-amino-3-hydroxy-5-methyl-
4-isoxazoleproprionic acid

• Glutamate (neurotransmitter) binds

to both
 Terminal boutons of Schaffer collaterals

NMDA and AMPA

receptors found together
on post-synaptic cell

Glutamate released from

Schaffer collaterals

Glu binds to NMDA and

AMPA receptors

NMDA and AMPA

receptors are ionophores
Pyramidal neuron (CA1)
 NMDA Receptor

Channel blocked by Mg++

Glutamate binds -> nothing

happens (ion channel blocked)

Mg++ removed only with

depolarization

Depolarization: activation of
AMPA receptor

Glu binds to AMPA, Na+ enters

cell, cell depolarizes
 NMDA Receptor

When cell depolarized,

Mg++ removed

Glu binds to NMDA

receptor site

Ion channel opens

Na+ and Ca++ move into

cell; K+ moves out of cell
 NMDA Receptor

Ca++ entry causes long-

lasting effects
 Some effects of Ca++ entry
• Activates kinases
– PKC, CaMKII
– build proteins

• Makes post-synaptic cell more responsive to

glutamate
– “AMPA-fication”
 Some effects of Ca++ entry
• “AMPA-fication”
– AMPA receptors more responsive to glutamate
(Glu binds more strongly)

– Some NMDA receptors change into AMPA

receptors

– Dendrites build more AMPA receptors

– When glutamate binds to AMPA, get larger

depolarization (larger response)
Growth of new AMPA
receptors

Growth of new spines and

synapses

Post-synaptic cell more

responsive to Glu

Hebbian synapse! Synapse

that increases its
effectiveness
Spines on a pyramidal neuron
•sites of synaptic contact
•grow and retract as a function
of learning/experience
 LTP and Learning/Memory
• Are LTP and learning related?
• Is LTP the neural basis of learning?
– model vs. mechanism
 LTP and Learning/Memory
• LTP only observed in brain areas known to be
involved in learning/memory
– Hippocampus
– Amygdala
– Cerebellum
– Prefrontal cortex
 LTP and Learning/Memory
• LTP can last for days or weeks
• Something like LTP has been recorded in vivo
after animals have learned a task
 LTP and Learning/Memory

• Induction – the process of getting LTP (the

procedure)
– induction of LTP – acquisition of information (learning)

• Expression – how the cell responds at a test

– expression of LTP –memory during a test
 LTP and Learning/Memory
• LTP induction, but not expression, blocked by
protein kinase inhibitors

– Protein kinase inhibitors block learning, not

memory, in animals
 LTP and Learning/Memory
• NMDA receptor antagonists block induction of
LTP; block learning

• NMDA antagonists have no effect on LTP

expression; no effects on memory
 LTP and Learning/Memory
• AMPA receptor antagonists block induction of
LTP; block learning

• AMPA antagonists block expression of LTP;

block memory

• Can you reason this through?

 LTP and Learning/Memory
• Knock-out mice:

– Tonegawa (MIT)
• Mice lack NMDA receptors in CA1 (pyramidal neurons)

• Mice do not learn hippocampus-dependent tasks

• Cannot induce LTP in hippocampal slices

 LTP and Learning/Memory
• Knock-in mice:

– Tsien (Princeton)
• “Doogie mouse”

• Extra NMDA receptors in CA1

• Faster learning in hippocampus-dependent tasks

• Faster induction of LTP in hippocampal slices