Suprachiasmatic nucleus
| Suprachiasmatic nucleus | |
|---|---|
 Suprachiasmatic nucleus in green | |
| Details | |
| Identifiers | |
| Latin | nucleus suprachiasmaticus |
| MeSH | D013493 |
| NeuroNames | 384 |
| NeuroLex ID | birnlex_1325 |
| TA98 | A14.1.08.911 |
| TA2 | 5720 |
| FMA | 67883 |
| Anatomical terms of neuroanatomy | |
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.[1][2] 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.[1][3] 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.[4][5] Early lesioning experiments in mouse, guinea pig, cat, and opossum established how removal of the SCN results in ablation of circadian rhythm in mammals.[4]
Moreover, the SCN 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.
Disruptions or damage to the SCN has been associated with different mood disorders and sleep disorders, suggesting the significance of the SCN in regulating circadian timing[6]
Neuroanatomy
The SCN is situated in the
The morphology of the SCN is species dependent.[8] 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.[8]
The nucleus can be divided into
In terms of projections, the core receives innervation via three main pathways, the retinohypothalamic tract, geniculohypothalamic tract, and projections from some raphe nuclei.[8] The dorsomedial SCN is mainly innervated by the core and also by other hypothalamic areas. Lastly, its output is mainly to the subparaventricular zone and dorsomedial hypothalamic nucleus which both mediate the influence SCN exerts over circadian regulation of the body.[8]
The most abundant peptides found within the SCN are
Circadian clock
Different organisms such as bacteria,[10] 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.[11] SCN lesioned hamsters lost their daily activity rhythms.[11] Further, when the SCN of a hamster was transplanted into an SCN lesioned hamster, the hamster adopted the rhythms of the hamster from which the SCN was transplanted.[11] Together, these experiments suggest that the SCN is sufficient for generating circadian rhythms in hamsters.
Later studies have shown that skeletal, muscle, liver, and lung tissues in rats generate 24-hour rhythms, which dampen over time when isolated in a dish, where the SCN maintains its rhythms.[12] 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.[13]
The SCN receives input from specialized
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).[16] A GABAergic mechanism is involved in the coupling of the ventral and dorsal regions of the SCN.[17]
Circadian rhythms of endothermic (warm-blooded) and ectothermic (cold-blooded) vertebrates
Information about the direct neuronal regulation of metabolic processes and
The SCN of endotherms and ectotherms
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
Behaviors controlled by the SCN of vertebrates
Significant research has been conducted on the genes responsible for controlling circadian rhythm, in particular within the SCN. Knowledge of the gene expression of
- Mice: Among vertebrates, it is known that mammals are endotherms that are capable of homeostatic thermoregulation. It has been shown that mice display thermosensitivity within the SCN. However, the regulation of body temperature in hypothermic mice is more sensitive to the amount of light in their environment.[21] Even while fasted, mice in darkened conditions and experiencing hypothermia maintained a stable internal body temperature.[21] In light conditions, mice showed a drop in body temperature under the same fasting and hypothermic conditions. Through analyzing genetic expression of Clock genes in wild-type and knockout strains, as well as analyzing the activity of neurons within the SCN and connections to proximate nuclei of the hypothalamus in the aforementioned conditions, it has been shown that the SCN is the center of control for circadian body temperature rhythm.[21] 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.[22] 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.[23] 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.[19]
Other signals from the retina
The SCN is one of many nuclei that receive nerve signals directly from the retina.
Some of the others are the
- 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 basal optic system also controls eye movements.[24]
- The pretectum controls the size of the pupil.
Genetic Basis of SCN Function
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.[25] Neurons isolated from the SCN have been shown to produce and sustain circadian rhythms in vitro,[26] suggesting that each individual neuron of the SCN can function as an independent circadian oscillator at the cellular level.[27] 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.[28]
Mammals
The SCN functions as a circadian biological clock in vertebrates including teleosts, reptiles, birds, and mammals..
As per and cry are transcribed and translated into PER and CRY, the proteins accumulate and form heterodimers in the cytoplasm. The heterodimers are phosphorylated at a rate that determines the length of the transcription-translation feedback loop (TTFL) and then translocate back into the nucleus where the phosphorylated PER-CRY heterodimers act on CLOCK and/or BMAL1 to inhibit their activity. Although the role of phosphorylation in the TTFL mechanism is known, the specific kinetics are yet to be elucidated.[33] 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.[34][35][36][32][37] 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.[38]
Electrophysiology
Neurons in the SCN fire action potentials in a 24-hour rhythm, even under constant conditions.[39] 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.[39] Thus, depolarization of SCN neurons via cAMP and calcium contributes to the magnitude of the rhythmic gene expression in the SCN.[39]
Further, the SCN synchronizes nerve impulses which spread to various
Many SCN neurons are sensitive to light stimulation via the retina.[41] 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.[42][43] 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.[39]
Clinical significance
Irregular sleep-wake rhythm disorder
Major depressive disorder
Alzheimer's disease
The functional disruption of the SCN can be observed in early stages of Alzheimer's disease (AD).[46] 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.[46] 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.[46]
See also
- Chronobiology
- Photosensitive ganglion cell
- Sense of time
- Retinohypothalamic tract
- Shift work sleep disorder
- Non-24-hour sleep–wake disorder
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