|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, which is 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. 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.
The SCN receives inputs from specialized photosensitive ganglion cells in the retina, via the retinohypothalamic tract. 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 24 hours 11 min). A GABAergic mechanism couples the ventral and dorsal regions of the SCN.
Information about the direct neuronal regulation of metabolic processes and circadian rhythm-controlled behaviors is not well known among either endothermic or ectothermic vertebrates, although extensive research has been done on the SCN in model animals such as the mammalian mouse and ectothermic reptiles, particularly lizards. The SCN is known to be involved not only in photoreception through innervation from the retinohypothalamic tract, but also in thermoregulation of vertebrates capable of homeostasis, as well as regulating locomotion and other behavioral outputs of the circadian clock within ectothermic vertebrates. The behavioral differences between both classes of vertebrates, when compared to the respective structures and properties of the SCN and various other nuclei proximate to the hypothalamus, provide insight into how these behaviors are the consequence of differing circadian regulation. Ultimately, many neuroethological studies must be done to completely ascertain the direct and indirect roles of the SCN on circadian-regulated behaviors of vertebrates.
Generally, external temperature does not influence endothermic animal behavior or circadian rhythm because of the ability of these animals to keep their internal body temperature constant through homeostatic thermoregulation; however, peripheral oscillators (see Circadian rhythm) in mammals are sensitive to temperature pulses and will experience resetting of the circadian clock phase and associated genetic expression, suggesting how peripheral circadian oscillators may be separate entities from one another despite having a master oscillator within the SCN. Furthermore, when individual neurons of the SCN from a mouse were treated with heat pulses, a similar resetting of oscillators was observed, but when an intact SCN was treated with the same heat pulse treatment the SCN was resistant to temperature change by exhibiting an unaltered circadian oscillating phase. In ectothermic animals, particularly the ruin lizard Podacris sicula, temperature has been shown to affect the circadian oscillators within the SCN. This reflects a potential evolutionary relationship among endothermic and ectothermic vertebrates, in how ectotherms rely on environmental temperature to affect their circadian rhythms and behavior and endotherms have an evolved SCN to essentially ignore external temperature and use photoreception as a means for entraining the circadian oscillators within their SCN. Additionally, the differences of the SCN between endothermic and ectothermic vertebrates suggest that the neuronal organization of the temperature-resistant SCN in endotherms is responsible for driving thermoregulatory behaviors in those animals differently from those of ectotherms, since they rely on external temperature for engaging in certain behaviors.
Significant research has been conducted on the genes responsible for controlling circadian rhythm, particularly within the SCN. Knowledge of the gene expression of Clock (Clk) and Period2 (Per2), two of the many genes responsible for regulating circadian rhythm within the individual cells of the SCN, has allowed for a greater understanding of how genetic expression influences the regulation of circadian rhythm-controlled behaviors. Studies on thermoregulation of ruin lizards and mice have informed some connections between the neural and genetic components of both vertebrates when experiencing induced hypothermic conditions. Certain findings have reflected how evolution of SCN both structurally and genetically has resulted in both classes of vertebrates engaging in characteristic and stereotyped thermoregulatory behavior.
The SCN is one of many nuclei that receive nerve signals directly from the retina.
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.
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.
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 Dick 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."
However, Swaab's research was "criticized on both methodological and conceptual grounds" in a 2003 review by Karori Mbugua. Among the issues Mbugua raises are: 1. sexual orientation was assessed by health care professionals by unknown means, rather than being self-reported. 2. While subjects "died of opportunistic infections resulting from AIDS, they were not matched for clinical diagnosis". Thus the diseases which actually killed the subjects were not controlled for.
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