|Brain: Suprachiasmatic nucleus|
| Suprachiasmatic nucleus is SC, at center left, labelled in blue.|
The optic chiasm is OC, just below, labelled in black.
|The left optic nerve and the optic tracts. (Suprachiasmatic nucleus not labeled, but diagram illustrates region.)|
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regulate many different body functions in a 24-hour cycle, using around 20,000 neurons.
The SCN, pine cone shaped and the size of a grain of rice, interacts with many other regions of the brain. It contains several cell types and several different peptides (including vasopressin and vasoactive intestinal peptide) and neurotransmitters.
Organisms in every kingdom of life—bacteria, plants, fungi, and animals—show genetically based 24-hour rhythms. Although all of these clocks appear to be based on a similar type of genetic feedback loop, the specific genes involved are thought to have evolved independently in each kingdom. Within the animal kingdom, however, a related set of genes are used by a wide variety of animals: the circadian genes in fruit flies, for example, are closely related to those in mammals.
Many aspects of mammalian behavior and physiology show circadian rhythmicity, including sleep, physical activity, alertness, hormone levels, body temperature, immune function, and digestive activity. Remarkably, all of these diverse rhythms are controlled by a single tiny brain area, the SCN, and are lost if the SCN is destroyed. In the case of sleep, for example, the total amount is maintained in rats with SCN damage, but the length and timing of sleep episodes become erratic. The importance of entraining organisms, including humans, to exogenous cues such as the light/dark cycle, is reflected by several circadian rhythm sleep disorders, where this process does not function normally.
The SCN also controls "slave oscillators" in the peripheral tissues, which exhibit their own ~24-hour rhythms, but are kept in synchrony by the SCN.
Neurons in the ventrolateral SCN (vlSCN) have the ability for light-induced gene expression. Melanopsin-containing ganglion cells in the retina have a direct connection to the ventrolateral SCN via the retinohypothalamic tract. 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 have an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24h 11min). A GABAergic mechanism couples the ventral and dorsal regions of the SCN.
Other signals from the retina
The SCN is one of four nuclei that receive nerve signals directly from the retina.
- 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 eye.
- 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 manner similar to that of flies.
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.
TIM has been identified in mammals, however, its function is still not determined. Mutations in TIM result in an inability to respond to zeitgebers, which is essential for resetting the biological clock.
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.
Sexual orientation and the SCN
In 1990, Professor D.F. Swaab carried out research into this part of hypothalamus searching for an organic basis for homosexuality in humans. He found the suprachiasmatic nucleus to be nearly twice the size in homosexual men as heterosexual men. This research was further confirmed by Laura S. Allen, who found the midsagittal plane of the anterior commissure of the hypothalamus to be one third larger in male homosexual subjects than in male heterosexuals.
Professor Swaab conducted a follow-on study in rats. Male rats were treated with ATD, an aromatase inhibitor, which prevents testosterone from converting to estradiol. The experiment compared three different populations, an untreated control group, a prenatally treated group, and a pre- and postnatally treated group. Adult rats that were treated with ATD prenatally showed no difference from the control group. Adult rats treated with ATD both pre- and postnatally, however, had significantly more neurons in the SCN than the controls. These male rats also exhibited bisexual behavior. According to the authors, "This observation supports the hypothesis that the increased number of vasopressin neurons found earlier in the SCN of adult homosexual men might reflect differences that took place in the interaction between sex hormones and the brain early in development."
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