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nucleus suprachiasmaticus
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Suprachiasmatic nucleus is 'SC', at center left, in blue OC, in black, is Optic Chiasm
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The left optic nerve and the optic tracts (Suprachiasmatic nucleus not labeled, but diagram illustrates region)
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The (SCN) is a region of the brain, located in the
Hypothalamus , that is responsible for controlling endogenous
Circadian Rhythms . The neuronal and hormonal activities it generates regulate many different body functions over a 24-hour period.
The SCN contains several cell types and several different
Peptide s (including
Vasopressin and
Vasoactive Intestinal Peptide ) and
Neurotransmitter s, and interacts with many other regions of the brain.
The SCN is situated in the
Hypothalamus immediately above the
Optic Chiasm on either side of the
Third Ventricle .
The SCN receives inputs from specialized photoreceptive retinal
Ganglion Cells , via the
Retinohypothalamic Tract .
Destruction of the SCN leads to a complete loss of circadian rhythm. Rats with damage to the SCN have no
Circadian Rhythm s, i.e., they sleep the same total amount, but at random times, for random lengths at a time.
The SCN also controls 'slave oscillators' in the peripheral tissues, which exhibit their own ~24 hour rhythms, but are crucially synchronized by the SCN.
The importance of entraining our bodies to an exogenous cue, such as light is reflected by several
Circadian Rhythm Sleep Disorders , where this process does not function normally.
Neurons in the ''ventrolateral SCN'' (vlSCN) have the ability for light-induced gene expression. If light is turned on at night, the vlSCN relays this information throughout the SCN, in a process called ''
Entrainment ''.
Neurons in the ''dorsomedial SCN'' (dmSCN) are believed to make an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24h 11min).
Melanopsin -containing
Ganglion Cell s in the
Retina have a direct connection to the SCN via the retino-hypothalamic tract.
The SCN sends information to other hypothalamic nuclei and the
Pineal Gland to modulate body temperature and production of hormones such as
Cortisol and
Melatonin .
The SCN is one of four nuclei that receive nerve signals directly from the retina.
The other three are the
Lateral Geniculate Nucleus (LGN), the
Superior Colliculus , and the
Pretectum :
- The ''LGN'' passes information about color, contrast, shape, and movement on to the Visual Cortex and itself signals to the SCN.
- The ''superior colliculus'' controls the movement and orientation of the eyeball.
- The ''pretectum'' controls the size of the Pupil .
The circadian rhythm in the SCN is generated by a
Gene Expression cycle in individual SCN neurons. This cycle has been well conserved through evolution, and is essentially similar in cells from many widely different organisms that show circadian rhythms.
For example, in the fruitfly ''
Drosophila '', the cellular circadian rhythm in neurons is controlled by two interlocked feedback loops.
- In the first loop, the bHLH transcription factors ''clock'' (''clk'') and ''cycle'' (''cyc'') drive the transcription of their own repressors ''period'' (''per'') and ''timeless'' (''tim''). PER and TIM proteins then accumulate in the cytoplasm, translocate into the nucleus at night, and turn off their own transcription, thereby setting up a 24 hour oscillation of transcription and translation.
- In the second loop, the transcription factors ''vrille'' (''vri'') and ''Pdp1'' are initiated by CLK/CYC. PDP1 acts positively on Clk transcription and negatively on VRI.
These genes encode various
Transcription Factors that trigger expression of other proteins. The products of ''clock'' and ''cycle'', called CLK and CYC, belong to the PAS-containing subfamily of the
Basic-helix-loop-helix (bHLH) family of
Transcription Factors , and form a
Heterodimer . This heterodimer (CLK-CYC) initiates the transcription of ''per'' and ''tim'', whose protein products dimerize and then inhibit their own expression by disrupting CLK-CYC-mediated transcription. This negative feedback mechanism gives a 24-hour rhythm in the expression of the clock genes. Many genes are suspected to be linked to circadian control by "E-box elements" in their promoters, as CLK-CYC and its homologs bind to these elements.
The 24-hr rhythm could be reset by light via the protein CRYPTOCHROME (CRY), which is involved in the circadian photoreception in ''Drosophila.'' CRY associates with TIM in a light-dependent manner that leads to the destruction of TIM. Without the presence of TIM for stabilization, PER is eventually destroyed during the day. As a result, the repression of CLK-CYC is reduced and the whole cycle reinitiates again.
In mammals, circadian clock genes behave in a similar manner.
CLOCK (circadian locomotor output cycles kaput) was first cloned in mouse and
BMAL -1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1) is the primary homolog of ''Drosophila'' CYC.
Three homologs of
PER (PER1-3) and two
CRY homologs (CRY1,2) have been identified.
TIM has been identified in mammals, however, its function is still not determined.
Recent research suggests that, outside the SCN clock, genes may have other important roles as well, including their influence on the effects of drugs of abuse such as
Cocaine .
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Neurons in the SCN fire
Action Potential s in a 24-hour rhythm. At mid-day, the firing rate reaches a maximum, and, during the night, it falls again. How the gene expression cycle (so-called the core clock) connects to the neural firing remains unknown.
Many SCN neurons are sensitive to light stimulation via the retina, and sustainedly firing action potentials during a light pulse (~30 seconds) in rodents. The photic response is likely linked to effects of light on circadian rhythms. In addition, focal application of melatonin can decrease firing activity of these neurons, suggesting that melatonin receptors present in the SCN mediate phase-shifting effects through the SCN.
Two contradictory reports exist about circadian variation of the cell calcium concentration. However, both reports agree that the resting calcium level is slightly higher during the day than at night.
