Suprachiasmatic nucleus

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Suprachiasmatic nucleus
Suprachiasmatic Nucleus.jpg
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. The SCN is the principal circadian pacemaker in mammals, responsible for generating circadian rhythms. [1] [2] Reception of light inputs from photosensitive retinal ganglion cells allow the SCN 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.

Contents

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 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. [7]

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 ventrolateral and dorsolateral portions, also known as the core and shell, respectively. [7] 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. [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 arginine-vasopressin (AVP), vasoactive intestinal polypeptide (VIP), and peptide histidine-isoleucine (PHI). Each of these peptides are localized in different regions. Neurons with AVP are found dorsomedially, whereas VIP-containing and PHI-containing neurons are found ventrolaterally. [9]

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 photosensitive ganglion cells in the retina via the retinohypothalamic tract. [14] 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. [14] When the retina receives light, the vlSCN relays this information throughout the SCN allowing entrainment , synchronization, of the person's or animal's daily rhythms to the 24-hour cycle in nature. [14] 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. [15]

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

A thermographic image of an ectothermic snake wrapping around the hand of an endothermic human Wiki stranglesnake.jpg
A thermographic image of an ectothermic snake wrapping around the hand of an endothermic human

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. [18] 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.

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 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. [18] 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. [18] In ectothermic animals, particularly the ruin lizard, Podarcis siculus, temperature has been shown to affect the circadian oscillators within the SCN. [19] 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. [18] In addition, 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.

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 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. [20] 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. [19] Certain findings have reflected how evolution of SCN both structurally and genetically has resulted in the engagement of characteristic and stereotyped thermoregulatory behavior in both classes of vertebrates.

Other signals from the retina

A variation of an eskinogram showing the influence of light and darkness on circadian rhythms and related physiology and behavior through the SCN in humans Circadian rhythm labeled.jpg
A variation of an eskinogram showing the influence of light and darkness on circadian rhythms and related physiology and behavior through the SCN in humans

The SCN is one of many nuclei that receive nerve signals directly from the retina.

Some of the others are the lateral geniculate nucleus (LGN), the superior colliculus, the basal optic system, and the pretectum:

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. [29] 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. [30] [31] [32] 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. [20] [32] In mammals, there are three known homologs for the period gene in Drosophila , namely per1 , per2 , and per3 .

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 parasympathetic and sympathetic nuclei. [40] 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. [40] Without the SCN, rhythms in body cells dampen over time, which may be due to lack of synchrony between cells. [39]

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

Irregular sleep-wake rhythm (ISWR) disorder is thought to be caused by structural damage to the SCN, decreased responsiveness of the circadian clock to light and other stimuli, and decreased exposure to light. [6] [44] 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. [6]

Major depressive disorder

Major depressive disorder (MDD) has been associated with altered circadian rhythms. [45] 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. [45]

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

Related Research Articles

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">PER3</span> Protein and coding gene in humans

The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associated with delayed sleep phase syndrome in humans.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Jürgen Aschoff</span>

Jürgen Walther Ludwig Aschoff was a German physician, biologist and behavioral physiologist. Together with Erwin Bünning and Colin Pittendrigh, he is considered to be a co-founder of the field of chronobiology.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

Michael Menaker, was an American chronobiology researcher, and was Commonwealth Professor of Biology at University of Virginia. His research focused on circadian rhythmicity of vertebrates, including contributing to an understanding of light input pathways on extra-retinal photoreceptors of non-mammalian vertebrates, discovering a mammalian mutation for circadian rhythmicity, and locating a circadian oscillator in the pineal gland of bird. He wrote almost 200 scientific publications.

Ueli Schibler is a Swiss biologist, chronobiologist and a professor at the University of Geneva. His research has contributed significantly to the field of chronobiology and the understanding of circadian clocks in the body. Several of his studies have demonstrated strong evidence for the existence of robust, self-sustaining circadian clocks in the peripheral tissues.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

In the field of chronobiology, the dual circadian oscillator model refers to a model of entrainment initially proposed by Colin Pittendrigh and Serge Daan. The dual oscillator model suggests the presence of two coupled circadian oscillators: E (evening) and M (morning). The E oscillator is responsible for entraining the organism’s evening activity to dusk cues when the daylight fades, while the M oscillator is responsible for entraining the organism’s morning activity to dawn cues, when daylight increases. The E and M oscillators operate in an antiphase relationship. As the timing of the sun's position fluctuates over the course of the year, the oscillators' periods adjust accordingly. Other oscillators, including seasonal oscillators, have been found to work in conjunction with circadian oscillators in order to time different behaviors in organisms such as fruit flies.

<span class="mw-page-title-main">Sato Honma</span>

Sato Honma is a Japanese chronobiologist who researches the biological mechanisms of circadian rhythms. She mainly collaborates with Ken-Ichi Honma on publications, and both of their primary research focuses are the human circadian clock under temporal isolation and the mammalian suprachiasmatic nucleus (SCN), its components, and associates. Honma is a retired professor at the Hokkaido University School of Medicine in Sapporo, Japan. She received her Ph.D. in physiology from Hokkaido University. She taught physiology at the School of Medicine and then at the Research and Education Center for Brain Science at Hokkaido University. She is currently the director at the Center for Sleep and Circadian Rhythm Disorders at Sapporo Hanazono Hospital and works as a somnologist.

Johanna H. Meijer is a Dutch scientist who has contributed significantly to the field of chronobiology. Meijer has made notable contributions to the understanding of the neural and molecular mechanisms of circadian pacemakers. She is known for her extensive studies of photic and non-photic effects on the mammalian circadian clocks. Notably, Meijer is the 2016 recipient of the Aschoff and Honma Prize, one of the most prestigious international prizes in the circadian research field. In addition to still unraveling neuronal mechanisms of circadian clocks and their applications to health, Meijer's lab now studies the effects of modern lifestyles on our circadian rhythm and bodily functions.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

Elizabeth Maywood is an English researcher who studies circadian rhythms and sleep in mice. Her studies are focused on the suprachiasmatic nucleus (SCN), a small region of the brain that controls circadian rhythms.

Ken-Ichi Honma is a Japanese chronobiologist who researches the biological mechanisms underlying circadian rhythms. After graduating from Hokkaido University School of Medicine, he practiced clinical psychiatry before beginning his research. His recent research efforts are centered around photic and non-photic entrainment, the structure of circadian clocks, and the ontogeny of circadian clocks. He often collaborates with his wife, Sato Honma, in work involving the mammalian suprachiasmatic nucleus (SCN), its components, and associated topics.

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