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Summary BBS2051 Case 1-6 + test questions
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Case 1 CampingLearning goals:
What is the circadian rhythm and what is its function?
The circadian rhythm is an internal biological clock which adapts to different times of
the day. It’s reset by Zeitgeber, environmental clues
Peripheral clock:
Infradian clock: Longer than circadian
Diurnal clock: Daytime period
Nocturnal clock: Darkness period, depends on seasons
Title rhythm: Depends on moon cycle, influences ocean
Cycle of moon and sun
Circadian: Period of 12 months
Hormonal levels
Melatonin: SCN directly interacts with the pineal gland though the sympathetic
neurons of the superior cervical ganglion; in turn, the rhythmic activity of the SCN
determines the release of melatonin, which directly correlated with day length. In both
nocturnal and diurnal animals, melatonin production peaks in the middle of the night,
between 24:00 and 03:00, inducing activity in the former and rest/ sleep the latter.
Melatonin plats several key roles, and can be considered the central ‘relayer’ which
conveys information about light-dark cycles. In mammals, melatonin is also essential
in the regulation of reproductive behaviour and sleep. In both primates and humans,
melatonin modulates adrenal glucocorticoid production, being able to supress cortisol
production.
Cortisol : In humans cortisol production usually increases during the night and shows
a peak of secretion in the morning, around 7:00-8:00, in this wat setting the endocrine
balance for the stress associated with waking. Glucocorticoids and cortisol can
modulate the expression of clock controlled genes in the liver, kidney and adipose
tissue.
The circadian rhythm of cortisol can be modified by environmental conditions,
including stressful events, light, and feeding.
o Acute stress leads to ACTH-induced release of cortisol that is not necessarily
in phase with the circadian pattern.
o Light exposure at night induces Per1 gene expression in the adrenal gland
and corticosterone release by activation of sympathetic fibers independently of
the hypothalamic-pituitary-adrenal axis.
o Restricted feeding triggers an anticipatory rise in circulating cortisol before
food access. This anticipatory peak is ACTH independent and distinct from the
circadian rhythm of cortisol controlled by the SCN clock
Body temperature:
In humans, the maximal body temperature is reached in the late afternoon and drops
to a minimum at the end of sleep phase. The circadian component in the body
temperature is under the control of the SCN, which project to the preoptic area. The
SCN is continuously
entrained by light signals from the retinohypothalamic tract and, in turn, synchronizes
circadian body temperature cycles to environmental light-dark cycles
, How is the CR regulated by signals?
o PER, BMAL1, CRY1; CRY2, ARNTL
The molecular clock machinery involves 24-oscillations of core clock components
known as clock genes.
Clock genes: Genes whose protein products are necessary for generating
circadian rhythmicity within individual cells.
Transcription factors: CLOCK and BMAL1, dimerize and bind to E-box
sequences in the promotors of other clock genes
PER1/2/3, CRY1/2 are activated by the TF
The molecular clockwork relies on transcriptional-translational feedback loops. The
main loop involves BMAL1 stimulating the transcription of PER and CRY genes. In
the auxiliary loops, ROR and REVERB stimulate and inhibit the transcription of
BMAL1
After reaching a given concentration in the cytoplasm, PERs and CRYs dimerize and
translocate into the nucleus to inhibit their own transcription mediated by
CLOCK/BMAL1 dimers. Auxiliary loops are composed of the circadian nuclear
receptors REV-ERBα-β and RORα-β-γ, which modulate negatively and positively the
circadian oscillations of Bmal1 expression
This cycle takes 24h
At night: much PER
During day: no PER1.
1. CLOCK and BMAL1 activate transcription of PER and CRY2.
2. PER and CRY to cytoplasm →dimerize →PER degraded to delay the cycle
3. PER and CRY inhibit CLOCK and BMAL1 (when light)
, 4. PER and CRY are degraded by β-TrCP and FBXL3, respectively (F-box
proteins)
5. PER and CRY don’t inhibit CLOCK and BMAL1 anymore →transcription of
PER and CRY begins again (when dark)
Phosphorylation: Kinases and jnfjn-B promote BMAL degradation
Fbox proteins are responsible for proteosome degradation
ROR and REV-ERBα control the expression of BMAL1
ROR initiates BMAL1 transcription
REV-ERBα inhibits BMAL 1transcription
PER
The ‘period’ gene produces the protein PER. PER build up during the night and
breaks down during the day.
NIGHT
1. PER binds to a protein called TIM, produced by the ‘timeless’ gene, and both
enter the nucleus.
2. Nuclear accumulation of PER
3. In the nucleus PER block period gene activity, stopping its own synthesis
a. PER inhibits CLK and CYK, encoded by the clock and cycle genes, are
two transcription factors that activate the period gene.
4. The ‘doubletime’ gene codes for the DBT protein that delays PER build-up(by
degrading PER), adjusting it to a 24 hour cycle.
WHEN MORNING ARRISES5.
5. TIM is degraded
a. Light activates the protein CRY (cryptochrome gene) → binds to TIM
→degradation
6. PER is vulnerable to phosphorylation by DBT →degradation ➔ PER
breakdown
What is the Suprachiasmatic nucleus (SCN)?
o How does the SCN regulate “other clocks”?
The clock in the suprachiasmatic nucleus, SCN, controls the sleep-wake cycle and
hormonal rhythms as well as a multitude of other circadian rhythms. Located in
anterior hypothalamus.
, The central clock is located in the SCN. The SCN consists of a heterogeneous
population of neuronal and glial cells distributed in two anatomic subdivisions
Ventral: Core, receiving retinal input
Dorsal: Shell, receiving dense input form the core
The core neurons express vasoactive intestinal polypeptide, VAP, and expresses
gastrin-releasing peptide. Most shell neurons express vasopressin. Most
neuropeptides colocalize with GABA and the synapses between SCN are GABAergic.
The near 24 hour rhythm of neuronal activity in the SCN is normally entrained to the
24 light dark cycle defined by the earth’s rotation. Light information is transmitted to
the SCN from specialized retinal ganglion cells that contain the photopigment
melanopsin. On activation by light, retinal axons release glutamate and pituitary
adenylate cyclase –activating polypeptide onto SCN neurons. Clock cells in the SCN
also receive dense input from the intergeniculate leaflet in the thalamus and the
median raphe nucleus, which play a modulatory role in regulating circadian rhythms.
Find more about this light pathway
RETINA, EYE TO SCN BY RETEOHYPOTHALAMIC TRACT, SCN CONNECTID
WITH PINEAL GLAND, WHICH PRODUCES MELATONIN ON SCN STIMULATION
Retina catches light, the eye is directly connected with the SCN by the
reteohypothalamic tract. The SCN is also connected with the pineal gland, which
produces melatonin on SCN stimulation.
The primary neuronal pathways underlying the circadian regulation of sleep-wake
cycles involves a dense SCN efferent projection to the adjacent sub paraventricular
zone, followed by a secondary projection to the dorsomedial hypothalamic nucleus,
which projects to other brain regions critical for regulating sleep and wakefulness. The
SCN also projects directly and indirectly to the paraventricular hypothalamic
nucleus to regulate corticosteroid secretion and synthesis of the hormone melatonin.
In addition to regulating circadian cycles of behaviour and endocrine function, the
SCN plays a hierarchical role in coordinating the timing and function of clocks located
in peripheral tissues.
Experiment more and eigner, Stephen and sucker
Destroy SCN to see if there is loss of rhythmicity
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