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Summary Cases Biorhythms in Homeostasis BBS2051
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Case 1PS: How does the circadian clock work?
Brainstorm:
• PER protein
• TIM protein
• Regulates hormone, sleep cycle, metabolism, body temperature, and behaviour …
influenced by light
• Communication between several internal clocks
• Melatonin → pineal gland
• Disruption of the circadian clock → possible consequences? Jet lag...
Learning Goals:
1. What is the circadian clock?
2. How does the circadian clock work at a molecular level? (gene level)
1. PER protein, TIM protein, CRY protein
3. Which factors can influence (and disrupt) the circadian clock?
4. Which processes are regulated by the circadian clock?
1. hormones, sleep cycle (melatonin), etc.
5. Apply the knowledge to the 2 subjects in the case
1
,LG-1 What is the circadian clock?
Living organisms have an internal biological clock, known as a circadian rhythm, which
adapts our physiology to different times of the day. Behaviour, body temperature, hormone
levels, sleep and metabolism are all affected by our circadian rhythm.
Circadian rhythm is a 24-hour cyclic rhythm found in animals that synchronizes with
presence and absence of light (solar light). Circadian clock is a molecular mechanism that
results in a circadian rhythm.
The central circadian clock
The circadian program is regulated at both a central and peripheral level. In mammals, the
central pacemaker or central clock is located in the suprachiasmatic nucleus (SCN) of the
hypothalamus (anterior of the hypothalamus, both sides) and functions as the master
circadian clock. The nuclei rest on each side of the third ventricle, just above the optic
chiasm. The retina receives photic input and relays this information to the SCN, which
synchronizes its own neuronal cellular clocks. The central clock regulates circadian rhythms
across the entire body via humoral factors and the peripheral autonomic nervous system. In
more detail, rhythmic signals from the SCN are distributed to the brain and the entire body
by two main pathways: the release of neurotransmitters and neuropeptides from terminals
of SCN efferents, a pathway critical for controlling hormonal rhythms (1) or a neurohumoral
pathway involving secretion of diffusible output signals regulating preferentially the rest-
activity rhythm. However, the capacity for circadian gene expression is widespread
throughout the body and most peripheral organs and tissues can express circadian
oscillations in isolation. Circadian system = more clocks
2
, The SCN consists of neuronal and glial cells distributed in a
ventral ‘core’ region (receiving retinal input) and a dorsal
‘shell’ region (receiving input from the core). The majority of
neurons express vasoactive intestinal polypeptide (VIP).
Most shell neurons express vasopressin.
The SCNs project most densely to the medial hypothalamus,
in particular the sub paraventricular zone. The SCN afferents
are mainly GABAergic, although also glutamatergic and
neuropeptidergic.
Extra-suprachiasmatic nucleus clocks / peripheral clocks
Peripheral clocks can be synchronized
both by the SCN and by environmental
cues, including feeding, physical activity
and temperature. Peripheral clocks in
different tissues control relevant
physiological outputs, such as glucose
production, fat storage and release of
hormones. These, in turn, function as
time- keeping cues for clocks in tissues
throughout the body, ultimately feeding
back to the SCN. Thus, the circadian
system of an organism is a web of
interconnected oscillators and feedback
loops.
- Retina and olfactory bulbs are the only extra-SCN clocks with strong oscillatory
capacities.
- Arcuate nucleus and dorsomedial hypothalamus involved in feeding and energy
metabolism.
- Cultured fibroblasts are resilient to large changes in temperature and overall
transcription rates. Activation of a multitude of intracellular pathways affects their
clockwork.
- In the liver, clock-controlled genes encode key enzymes involved in hepatic
metabolism of fatty acids, cholesterol, bile acids, amino acids and xenobiotics.
- The adipose tissue also exhibits robust oscillations of core clock components,
controlling the circadian expression of many transcription factors. The lipoprotein
lipase displays a rhythmic activity in adipose tissue. Moreover, the adipose tissue
secretes several hormones termed adipokines, including leptin and adiponectin,
involved in the regulation of energy balance.
- Heart rate
- Glycemia rhythm (liver)
- Leptin rhythm
- Muscular strength rhythm
- Insulin rhythm (pancreas)
3
, In the SCN, electrical activity and per1
expression peak during daytime, while
the corresponding peaks occur at night in
extra-SCN oscillators.
4
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