This document contains a summary and elaboration of the learning goals of task 3 of the course Sleep and Sleep Disorders. The literature used for this task is new compared to previous years.
Task 3: Shift problems
How are circadian rhythms regulated?
Circadian rhythms = biological patterns (behaviors + physiological processes) that follow a daily
pattern/have cycles of about 24 hours. Some of them are passive responses to changes in illumination
(sunlight/darkness), others are controlled by mechanisms within the organism/internal clocks. A free-
running clock with a cycle of approximately 25 hours sleep and wakefulness (free-running period is
largely genetically determined).
Regular daily variation in illumination levels normally keeps the clock adjusted to 24 hours ->
light serves as a zeitgeber -> it synchronizes the endogenous rhythm
o If an animal is exposed to bright light soon after dusk, the biological clock is set back to
an earlier time, but when the light occurs late at night, the biological clock is set ahead
to a later time (as if dawn had already come)
Under constant illumination our biological clocks will run free -> most people will begin to live a
day that is approximately 25 hours long.
o The morning light, acting as a zeitgeber, resets the clock
The circadian system adjusts or fine-tunes physiology and behavior to the profound yet
predictable demands of the 24h day/night cycle.
o Responses to medication may be very different at different times of the day
The suprachiasmatic nucleus (SCN)
= a specific region/two paired nuclei in the hypothalamus that
receives light information from the environment via afferent
projections from the retina through the retinohypothalamic tract
and uses it to entrain behaviors to a 24-hour light/dark cycle.
Melanopsin, a photochemical, is responsible for providing
information about the ambient level of light that
synchronizes circadian rhythms.
o Is present in ganglion cells (neurons whose axons
transmit information from the eyes to the rest of the
brain) -> melanopsin-containing ganglion cells are
sensitive to light and their axons terminate in the
SCN
They also terminate in the region of the midbrain that controls the response of the
pupils to change in the level of illumination
o People who have become blind (loss of rods and cones) can still show normal circadian
rhythms.
Lesions of the SCN disrupt daily patterns of wheel running, drinking and hormonal secretion in
rats.
The SCN also provides the primary control over the timing of sleep cycles -> lesions of the SCN
abolish patterns of sleep, but rats with lesions still obtain the same amount of sleep than normal
animals do -> lesions disrupt the circadian control of sleep, but do not affect its homeostatic
control
Light is the major external time cue in mammals -> entrainment is restricted to light-dark (LD) cycles
that are close to 24 hours in duration.
The range of entrainment varies from species to species and is dependent on the experimental
conditions (e.g., intensity of LD cycle, whether period of LD cycle is changed gradually/rapidly)
, If the period of the LD cycle is too short or too long for entrainment to occur, the circadian
rhythm will free run, following the period of the endogenous pacemaker rather than the external
environment
Also, entrainment by nonphotic signals, like scheduled bedtimes/mealtimes, various timed social
cues -> sleep and social schedules may phase-shift circadian clock and physical exercise during
the night can produce a phase delay in human circadian rhythms. Exercise during the morning
can accelerate entrainment following a phase advance in the sleep-wake cycle.
Efferent axons of the SCN responsible for organizing cycles of sleep and waking terminate in the
subparaventricular zone (SPZ) (region dorsal to the SCN).
Lesions ventral part SPZ -> disruption of circadian rhythms of sleep and waking
The ventral SPZ projects to the dorsomedial nucleus of the hypothalamus (DMH), which in turn
projects to several brain regions:
o Projections to the vlPOA are inhibitory and thus inhibit sleep
o Projections to the orexinergic neurons are excitatory and promote wakefulness
The activity of these connections varies across the day/night cycle -> in diurnal
animals: high during the day, low during the night.
The SCN can also control circadian rhythms of sleep and waking by secretion of chemicals that diffuse
through the brain’s extracellular fluid.
Evidence from transplantation study: destroying SCN in hamsters -> abolishment of circadian
rhythms -> implementation of donor SCN tissue in a capsule a few weeks later -> neurons inside
capsule were not able to establish synaptic connections with surrounding tissue, but transplants
reestablished circadian rhythms.
o The chemical signal may be prokineticin 2 in a subset of SCN neurons. Presumably, the
chemicals secreted by the cells in the SCN affect rhythms of sleep and waking by
diffusing into the SPZ and binding with receptors on neurons located there.
Studies have shown daily activity rhythms or day/night fluctuations in the activity of the SCN -> due to
activity within individual neurons, which have individual, independent circadian rhythms in activity.
Cells in the SCN have their own inbuilt biological clock
Cells in the SCN produce the proteins CLOCK and BMAL1 which bind together -> promote the
expression of genes period/PER and cryptochrome/CRY -> the produced protein products of PER
and CRY bind together and inhibit the actions of clock and BMAL1 -> suppression of the
expression of PER and CRY -> PER and CRY proteins begin to degrade -> CLOCK/BMAL1 can
promote PER and CRY transcription again
o This process takes about 24 hours to complete, before it repeats
o Involves at least 7 genes + 2 feedback loops -> when one of the proteins produced by
the first loop reaches a sufficient level, it starts the second loop, which eventually inhibits
the production of the proteins in the first loop, and the cycle begins again.
o Thus, the intracellular rhythm is regulated by the time it takes to produce and degrade a
set of proteins.
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