The Chronobiology of Sleep
• Circadian clocks evolved to maintain appropriate periods of sleep and
wakefulness in spite of the variable amount of daylight and darkness in different
seasons and at different places on the planet.
• To synchronize physiological processes with the day-night cycle (called
photoentrainment), the biological clock must detect decreases in light levels as
night approaches.
• The receptors that sense these light changes are within the ganglion and amacrine
cell layers of retinas
• These peculiar retinal photoreceptors contain a novel photopigment called
melanopsin.
• Light resets the oscillations in the suprachiasmatic nucleus (SCN) through a mechanism involving
melanopsin-containing retinal ganglion cells that project directly to the SCN via the retino-hypothalamic
tract.
• Melanopsin in retinal ganglion cells in the eye respond to light (natural or artificial) and transmit signals to
the SCN. Through an indirect pathway, circadian information reaches the pineal gland where the hormone
melatonin is produced
• The light-dependent regulation of melatonin secretion depends on an indirect pathway that includes the
SCN, PVN, and the sympathetic system
Pathway involving regulation of melatonin secretion by
light
Mechanism of reciprocal interactions between the suprachiasmatic nucleus (SCN) and melatonin
IML-intermediolateral cell column; SCG-superior cervical ganglion; AANAT-arylalkylamine N-acetyltransferase; CaMK-
calmodulin kinase; CREB-cyclic adenosine monophosphate (cAMP) responsive element binding protein; 5-HTP-5-
hydroxytryptophan; HI-OMT-hydroxyl indol-O-methyltransferase; NE-norepinephrine; NO-nitric oxide; PAC2- pituitary
adenylate cyclase activating polypeptide receptor 2; PKA-protein kinase A
• Light activates photosensitive retinal ganglion cells that express melanopsin and project to the SCN via
the retinohypothalamic tract (RHT).
• The RHT axons release glutamate and pituitary adenylate cyclase activating polypeptide (PACAP), which
mediate entrainment of clock gene expression in the SCN.
• The SCN contains GABAergic neurons that send a direct inhibitory projection to neurons of the
paraventricular nucleus (PVN) of the hypothalamus.
• These PVN neurons activate preganglionic neurons of the intermediolateral cell column (IML) that, via
the superior cervical ganglion (SCG), activate melatonin secretion by the pineal gland.
• Norepinephrine, acting via beta-1 (1) receptors, increases activity of arylalkylamine N-acetyltransferase
(AA-NAT), the critical enzyme for melatonin synthesis.
• Circulating melatonin, acting via melatonin (MT)1 and MT2 receptors, inhibits firing of the SCN
(promoting sleep) and resets the circadian pacemaker.
Stages of Sleep
• Nathaniel Kleitman is the father of sleep research and co-discoverer of REM sleep
• There are four stages of sleep: Non-Random Eye Movement (NREM) sleep (Stages 1, 2 & 3)
and REM sleep.
• During the night, these stages of NREM (quiet sleep) alternate with periods of REM
(dreaming) sleep. Quiet sleep is important because it helps restore the body,
while REM sleep restores the mind and is important for both learning and
memory.
• Periods of wakefulness occur before and intermittently throughout the various sleep stages
or as one shifts sleeping position.
• If you’re fully awake, an EEG records a messy, irregular scribble of activity. Once your eyes
are closed and your brain no longer receives visual input, brain waves settle into a steady
and rhythmic pattern of about 10 cycles per second. It is the alpha-wave pattern,
characteristic of calm, relaxed wakefulness
Stage N1
• The transition stage from wakefulness into light sleep EEG brain wave pattern during sleep
• The predominant brain waves are theta waves (four to seven
cycles per second)
• Body temperature begins to drop, muscles relax, and eyes often
move slowly from side to side.
• People in stage N1 sleep lose awareness of their surroundings,
but they are easily jarred awake.
Stage N2
• First stage of true sleep
• Eyes are still, heart rate and breathing are slower than when awake.
• Brain’s electrical activity is irregular. Large, slow waves intermingle with brief bursts of activity
called sleep spindles (which involves organizing memories for long-term storage).
• The EEG tracings also show a pattern called a K-complex, which represents a sort of built-in
vigilance system that keeps you poised to awaken if necessary.
• K-complexes can also be provoked by certain sounds or other external or internal stimuli.
Stage N3 (deep sleep, or slow-wave sleep)
• Large, slow brain waves called delta waves become a major feature
• Breathing becomes more regular, blood pressure falls, and the pulse slows to about 20% to
30% below the waking rate.
• The brain is less responsive to external stimuli, making it difficult to wake the sleeper
• At the beginning of this stage, the pituitary gland releases a pulse of growth hormone that
stimulates tissue growth and muscle repair. Researchers have also detected increased
blood levels of substances that activate immune system, raising the possibility that deep
sleep helps the body defends itself against infection.
Dreaming (REM) sleep
• Dreaming occurs during REM (rapid eye movement) sleep, which has been
described as an “active brain in a paralyzed body.”
• Brain races, thinking and dreaming, as eyes dart back and forth rapidly behind
closed lids. Body temperature rises, blood pressure increases, and heart rate
and breathing speed up to daytime levels
• The sympathetic nervous system, which creates the fight-or-flight response, is
twice as active as when awake.
• REM or dreaming sleep restores mind and facilitates learning and
memory.
EEG signals during sleep and wake stage
Sleep Cycle
• A sleep cycle is the progression through the various stages of NREM sleep to REM sleep
before beginning the progression again with NREM sleep.
• A complete sleep cycle takes an average of 90 to 110 minutes, with each stage lasting
between 5 to 15 minutes. The first sleep cycles each night have relatively short REM
sleeps and long periods of deep sleep but later in the night, REM periods lengthen and
deep sleep time decreases.
• Sleep play essential role in many vital physiologic functions including development,
energy conservation, brain waste clearance, and modulation of immune responses,
cognition, performance, disease, vigilance, and psychological conditions