Suprachiasmatic nucleus

The suprachiasmatic nucleus (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 peptides (including vasopressin and vasoactive intestinal peptide) and neurotransmitters, and interacts with many other regions of the brain.

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Location

The SCN is situated in the hypothalamus immediately above the optic chiasm on either side of the third ventricle.

Circadian effects

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 rhythms, 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 daylight, 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 cells in the retina have a direct connection to the SCN via the retinohypothalamic 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.

Other signals from the retina

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.

Gene expression

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.

Fruitfly

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.

Mammals

In mammals, circadian clock genes behave in a similar manner.

CLOCK (circadian locomotor output cycles kaput) was first cloned in mouse and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1) is the primary homolog of Drosophila CYC.

Three homologs of PER (PER1, PER2, and PER3) and two CRY homologs (CRY1 and CRY2) 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.^[1][2]

Electrophysiology

Neurons in the SCN fire action potentials 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.

Calcium dynamics

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.

See also

• Chronobiology
• Sense of time

References

1. ^ Yuferov V, Butelman E, Kreek M (2005). "Biological clock: biological clocks may modulate drug addiction". Eur J Hum Genet 13 (10): 1101-3. PMID 16094306.
2. ^ Manev H, Uz T (2006). "Clock genes as a link between addiction and obesity". Eur J Hum Genet 14 (1): 5. PMID 16288309.