Супрахиазматическое ядро: главный регулятор циркадных ритмов

Part of the brain's hypothalamus

The suprachiasmatic nucleus or nuclei (SCN) is a small region of the brain in the hypothalamus, situated directly above the optic chiasm. It is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. Reception of light inputs from photosensitive retinal ganglion cells allow it to coordinate the subordinate cellular clocks of the body and entrain to the environment. The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24 hour cycle. The idea that the SCN is the main circadian pacemaker in mammals was proposed by Robert Moore, who conducted experiments using radioactive amino acids to find where the termination of the retinohypothalamic projection occurs in rodents. Early lesioning experiments in mouse, guinea pig, cat, and opossum established how removal of the SCN results in ablation of circadian rhythm in mammals.

The SCN is situated in the anterior part of the hypothalamus immediately dorsal, or superior (hence supra) to the optic chiasm bilateral to (on either side of) the third ventricle. It consists of two nuclei composed of approximately 10,000 neurons. Distribution of different cell phenotypes across specific SCN regions, such as the concentration of VP IR neurons, can cause the shape of the SCN to change. These regions differ in their expression of the clock genes, the core expresses them in response to stimuli whereas the shell expresses them constitutively. In terms of projections, the core receives innervation via three main pathways, the retinohypothalamic tract, geniculohypothalamic tract, and projections from some raphe nuclei.

Different organisms such as bacteria, plants, fungi, and animals, show genetically based near 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. Many aspects of mammalian behavior and physiology show circadian rhythmicity, including sleep, physical activity, alertness, hormone levels, body temperature, immune function, and digestive activity. Early experiments on the function of the SCN involved lesioning the SCN in hamsters. SCN lesioned hamsters lost their daily activity rhythms. Together, these data suggest a model whereby the SCN maintains control across the body by synchronizing "slave oscillators," which exhibit their own near 24 hour rhythms and control circadian phenomena in local tissue. The SCN receives input 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. 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 is involved in the coupling of 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 homeothermy 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 as well as 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.

In general, external temperature does not influence endothermic animal 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. This reflects a potential evolutionary relationship among endothermic and ectothermic vertebrates as ectotherms rely on environmental temperature to affect their circadian rhythms and behavior while endotherms have an evolved SCN that is resistant to external temperature fluctuations and uses photoreception as a means for entraining the circadian oscillators within their SCN. This circadian control, thus, includes both direct and indirect influence of many of the thermoregulatory behaviors that mammals engage in to maintain homeostasis. Ruin lizards: Several studies have been conducted on the genes expressed in circadian oscillating cells of the SCN during various light and dark conditions, as well as effects from inducing mild hypothermia in reptiles. In terms of structure, the SCNs of lizards have a closer resemblance to those of mice, possessing a dorsomedial portion and a ventrolateral core. However, genetic expression of the circadian related Per2 gene in lizards is similar to that in reptiles and birds, despite the fact that birds have been known to have a distinct SCN structure consisting of a lateral and medial portion. Studying the lizard SCN because of the lizard's small body size and ectothermy is invaluable to understanding how this class of vertebrates modifies its behavior within the dynamics of circadian rhythm, but it has not yet been determined whether the systems of cold blooded vertebrates were slowed as a result of decreased activity in the SCN or showed decreases in metabolic activity as a result of hypothermia. The pretectum controls the size of the pupil.

The SCN is the central circadian pacemaker of mammals, serving as the coordinator of mammalian circadian rhythms. Neurons in an intact SCN show coordinated circadian rhythms in electrical activity. Neurons isolated from the SCN have been shown to produce and sustain circadian rhythms in vitro, suggesting that each individual neuron of the SCN can function as an independent circadian oscillator at the cellular level. Each cell of the SCN synchronizes its oscillations to the cells around it, resulting in a network of mutually reinforced and precise oscillations constituting the SCN master clock.

The SCN functions as a circadian biological clock in vertebrates including teleosts, reptiles, birds, and mammals. In mammals, the rhythms produced by the SCN are driven by a transcription translation negative feedback loop (TTFL) composed of interacting positive and negative transcriptional feedback loops. Within the nucleus of an SCN cell, the genes Clock and Bmal1 (mop3) encode the BHLH PAS transcription factors CLOCK and BMAL1 (MOP3), respectively. CLOCK and BMAL1 are positive activators that form CLOCK BMAL1 heterodimers. These heterodimers then bind to E boxes upstream of multiple genes, including per and cry, to enhance and promote their transcription and eventual translation. As a result, PER and CRY function as negative repressors and inhibit the transcription of per and cry. Over time, the PER CRY heterodimers degrade and the cycle begins again with a period of about 24.5 hours. The integral genes involved, termed “clock genes," are highly conserved throughout both SCN bearing vertebrates like mice, rats, and birds as well as in non SCN bearing animals such as Drosophila.

Neurons in the SCN fire action potentials in a 24 hour rhythm, even under constant conditions. At mid day, the firing rate reaches a maximum, and, during the night, it falls again. Rhythmic expression of circadian regulatory genes in the SCN requires depolarization in the SCN neurons via calcium and cAMP. The sympathetic nuclei drive glucocorticoid output from the adrenal gland which activates Per1 in the body cells, thus resetting the circadian cycle of cells in the body. The photic response is likely linked to effects of light on circadian rhythms. In addition, application of melatonin in live rats and isolated SCN cells can decrease the firing rate of these neurons. Variances in light input due to jet lag, seasonal changes, and constant light conditions all change the firing rhythm in SCN neurons demonstrating the relationship between light and SCN neuronal functioning. People who tend to stay indoors and limit their exposure to light experience decreased nocturnal melatonin production. The decrease in melatonin production at night corresponds with greater expression of SCN generated wakefulness during night, causing irregular sleep patterns. Patients with MDD have weaker rhythms that express clock genes in the brain. When SCN rhythms were disturbed, anxiety like behavior, weight gain, helplessness, and despair were reported in a study conducted with mice. Abnormal glucocorticoid levels occurred in mice with no Bmal1 expression in the SCN. Changes in the SCN and melatonin secretion are major factors that cause circadian rhythm disturbances. These disturbances cause the normal physiology of sleep to change, such as the biological clock and body temperature during rest. Patients with AD experience insomnia, hypersomnia, and other sleep disorders as a result of the degeneration of the SCN and changes in critical neurotransmitter concentrations.