Editing Suprachiasmatic nucleus

{{Short description|Part of the brain's hypothalamus}}
{{Use American English|date = March 2019}}
{{Infobox Brain
|Name = Suprachiasmatic nucleus 
|Latin = nucleus suprachiasmaticus 
|Image = 
|Caption = 
|Image2 = Suprachiasmatic Nucleus.jpg
|Caption2 = Location of suprachiasmatic nucleus{{brk}}{{midsize|{{em|(in green between [[optic chiasm]] and [[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 responsible for [[circadian rhythm|regulating sleep cycles]] in animals.<ref name="Hastings">{{Cite journal |last1=Hastings |first1=Michael H. |last2=Maywood |first2=Elizabeth S. |last3=Brancaccio |first3=Marco |date=August 2018 |title=Generation of circadian rhythms in the suprachiasmatic nucleus |url=https://www.nature.com/articles/s41583-018-0026-z |journal=Nature Reviews Neuroscience |language=en |volume=19 |issue=8 |pages=453–469 |doi=10.1038/s41583-018-0026-z |pmid=29934559 |s2cid=256745076 |issn=1471-0048|url-access=subscription }}</ref><ref name="Hastings2">{{cite journal |last1=Hastings |first1=MH |last2=Maywood |first2=ES |last3=Brancaccio |first3=M |title=The Mammalian Circadian Timing System and the Suprachiasmatic Nucleus as Its Pacemaker. |journal=Biology |date=11 March 2019 |volume=8 |issue=1 |page=13 |doi=10.3390/biology8010013 |pmid=30862123|doi-access=free |pmc=6466121 }}</ref> Reception of light inputs from photosensitive [[retinal ganglion cell]]s allow it to coordinate the subordinate cellular clocks of the body and [[Entrainment (chronobiology)|entrain]] to the environment.<ref name="Hastings" /><ref>{{Citation |last1=Weaver |first1=David R. |title=Chapter 39 - Circadian Timekeeping |date=2013-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780123858702000391 |work=Fundamental Neuroscience (Fourth Edition) |pages=819–845 |editor-last=Squire |editor-first=Larry R. |access-date=2023-04-25 |place=San Diego |publisher=Academic Press |language=en |isbn=978-0-12-385870-2 |last2=Emery |first2=Patrick |editor2-last=Berg |editor2-first=Darwin |editor3-last=Bloom |editor3-first=Floyd E. |editor4-last=du Lac |editor4-first=Sascha}}</ref> The neuronal and hormonal activities it generates regulate many different body functions in an approximately 24-hour cycle.

The SCN also interacts with many other regions of the brain. It contains several cell types, [[neurotransmitter]]s and [[peptide]]s, including [[vasopressin]] and [[vasoactive intestinal peptide]].

Disruptions or damage to the SCN has been associated with different [[mood disorder]]s and [[sleep disorder]]s, suggesting the significance of the SCN in regulating [[Circadian rhythm|circadian timing]].<ref name=":3">{{Citation |last1=Ma |first1=Melinda A. |title=Neuroanatomy, Nucleus Suprachiasmatic |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK546664/ |work=StatPearls |access-date=2023-04-25 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31536270 |last2=Morrison |first2=Elizabeth H.}}</ref>

==Neuroanatomy==
The SCN is situated in the [[anterior]] part of the hypothalamus immediately [[Anatomical terms of location#Dorsal and ventral|dorsal]], or ''superior'' (hence [[Supra (grammar)|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.<ref name=":2"/>

The [[Morphology (biology)|morphology]] of the SCN is species dependent.<ref name=lpm>{{Cite journal |last=Morin |first=Lawrence P. |date=May 2013 |title=Neuroanatomy of the extended circadian rhythm system |journal=Experimental Neurology |volume=243 |pages=4–20 |doi=10.1016/j.expneurol.2012.06.026 |issn=1090-2430 |pmc=3498572 |pmid=22766204}}</ref> 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.<ref name=lpm />

The nucleus can be divided into [[ventrolateral]] and [[dorsolateral]] portions, also known as the core and shell, respectively.<ref name=":2">{{Citation |last1=Ma |first1=Melinda A. |title=Neuroanatomy, Nucleus Suprachiasmatic |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK546664/ |work=StatPearls |access-date=2023-04-09 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31536270 |last2=Morrison |first2=Elizabeth H.}}</ref> 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]].<ref name=lpm /> 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.<ref name=lpm />

The most abundant peptides found within the SCN are [[arginine-vasopressin]] (AVP), [[Vasoactive intestinal peptide|vasoactive intestinal polypeptide]] (VIP), and [[Peptide histidine isoleucine|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.<ref>{{Cite journal |last=Reuss |first=Stefan |date=1996-08-01 |title=Components and connections of the circadian timing system in mammals |url=https://doi.org/10.1007/s004410050652 |journal=Cell and Tissue Research |language=en |volume=285 |issue=3 |pages=353–378 |doi=10.1007/s004410050652 |pmid=8772150 |s2cid=17338595 |issn=1432-0878|url-access=subscription }}</ref>

==Circadian clock==
{{Main|Circadian clock}}
Different organisms such as bacteria,<ref>{{cite journal|vauthors=Clodong S, Dühring U, Kronk L, Wilde A, Axmann I, Herzel H, Kollmann M|title=Functioning and robustness of a bacterial circadian clock | journal = Molecular Systems Biology|volume=3|issue=1|pages=90|year=2007|pmid =17353932|pmc=1847943|doi = 10.1038/msb4100128|author8= Clodong S, Dühring U, Kronk L, Wilde A, Axmann I, Herzel H, Kollmann M }}</ref> 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.<ref name=":4">{{Cite journal |last1=Ralph |first1=Martin R. |last2=Foster |first2=Russell G. |last3=Davis |first3=Fred C. |last4=Menaker |first4=Michael |date=1990-02-23 |title=Transplanted Suprachiasmatic Nucleus Determines Circadian Period |url=http://dx.doi.org/10.1126/science.2305266 |journal=Science |volume=247 |issue=4945 |pages=975–978 |doi=10.1126/science.2305266 |pmid=2305266 |issn=0036-8075|url-access=subscription }}</ref> SCN lesioned hamsters lost their daily activity rhythms.<ref name=":4" /> 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.<ref name=":4" /> 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.<ref>{{Cite journal |last1=Yamazaki |first1=Shin |last2=Numano |first2=Rika |last3=Abe |first3=Michikazu |last4=Hida |first4=Akiko |last5=Takahashi |first5=Ri-ichi |last6=Ueda |first6=Masatsugu |last7=Block |first7=Gene D. |last8=Sakaki |first8=Yoshiyuki |last9=Menaker |first9=Michael |last10=Tei |first10=Hajime |date=2000-04-28 |title=Resetting Central and Peripheral Circadian Oscillators in Transgenic Rats |url=http://dx.doi.org/10.1126/science.288.5466.682 |journal=Science |volume=288 |issue=5466 |pages=682–685 |doi=10.1126/science.288.5466.682 |pmid=10784453 |issn=0036-8075|url-access=subscription }}</ref> 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.<ref>{{cite journal|vauthors=Bernard S, Gonze D, Cajavec B, Herzel H, Kramer A|title = Synchronization-induced rhythmicity of circadian oscillators in the suprachiasmatic nucleus | journal = PLOS Computational Biology | volume = 3 | issue = 4|pages=e68|date=April 2007|pmid =17432930|pmc=1851983 | doi = 10.1371/journal.pcbi.0030068 | bibcode = 2007PLSCB...3...68B |doi-access = free }}</ref>

The SCN receives input from specialized [[photosensitive ganglion cell]]s in the retina via the [[retinohypothalamic tract]].<ref name=":5">{{Cite journal |last1=Miller |first1=Joseph D. |last2=Morin |first2=Lawrence P. |last3=Schwartz |first3=William J. |last4=Moore |first4=Robert Y. |date=1996 |title=New Insights Into the Mammalian Circadian Clock |journal=Sleep |volume=19 |issue=8 |pages=641–667 |doi=10.1093/sleep/19.8.641 |pmid=8958635 |issn=1550-9109|doi-access=free }}</ref> Neurons in the ''ventrolateral SCN'' (vlSCN) have the ability for light-induced gene expression. [[Melanopsin]]-containing [[retinal ganglion cell|ganglion cell]]s in the [[retina]] have a direct connection to the ventrolateral SCN via the retinohypothalamic tract.<ref name=":5" /> When the retina receives light, the vlSCN relays this information throughout the SCN allowing ''[[entrainment (chronobiology)|entrainment]]'', synchronization, of the person's or animal's daily rhythms to the 24-hour cycle in nature.<ref name=":5" /> 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.<ref name="pmid15087208">{{cite journal | vauthors = Reid KJ, Chang AM, Zee PC | title = Circadian rhythm sleep disorders | journal = The Medical Clinics of North America | volume = 88 | issue = 3 | pages = 631–51, viii | date = May 2004 | pmid = 15087208 | doi = 10.1016/j.mcna.2004.01.010 | pmc = 3523094 }}</ref>

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&nbsp;hours 11&nbsp;min).<ref>{{Cite web|url=https://news.harvard.edu/gazette/story/1999/07/human-biological-clock-set-back-an-hour/|title=Human Biological Clock Set Back an Hour|date=1999-07-15|website=Harvard Gazette|language=en-US|access-date=2019-01-28}}</ref> A GABAergic mechanism is involved in the coupling of the ventral and dorsal regions of the SCN.<ref>{{cite journal |last1=Azzi |first1=A |last2=Evans |first2=JA |last3=Leise |first3=T |last4=Myung |first4=J |last5=Takumi |first5=T |last6=Davidson |first6=AJ |last7=Brown |first7=SA |title=Network Dynamics Mediate Circadian Clock Plasticity. |journal=Neuron |date=18 January 2017 |volume=93 |issue=2 |pages=441–450 |doi=10.1016/j.neuron.2016.12.022 |pmid=28065650 |pmc=5247339 }}</ref>

==Circadian rhythms of endothermic (warm-blooded) and ectothermic (cold-blooded) vertebrates==

[[Image:Wiki stranglesnake.jpg|thumb|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.<ref name="taka">{{cite journal | vauthors = Buhr ED, Yoo SH, Takahashi JS | title = Temperature as a universal resetting cue for mammalian circadian oscillators | journal = Science | volume = 330 | issue = 6002 | pages = 379–85 | date = October 2010 | pmid = 20947768 | pmc = 3625727 | doi = 10.1126/science.1195262 | bibcode = 2010Sci...330..379B }}</ref> 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.<ref name="taka" /> 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.<ref name="taka"/> In ectothermic animals, particularly the [[ruin lizard]], ''Podarcis siculus'', temperature has been shown to affect the circadian oscillators within the SCN.<ref name="mag">{{cite journal | vauthors = Magnone MC, Jacobmeier B, Bertolucci C, Foà A, Albrecht U | title = Circadian expression of the clock gene Per2 is altered in the ruin lizard (Podarcis sicula) when temperature changes | journal = Brain Research. Molecular Brain Research | volume = 133 | issue = 2 | pages = 281–5 | date = February 2005 | pmid = 15710245 | doi = 10.1016/j.molbrainres.2004.10.014 | hdl = 11392/1198011 | url = http://doc.rero.ch/record/4325/files/1_albrecht_cec.pdf }}</ref> 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.<ref name="taka" /> 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 gene|''Clock'' (''Clk'')]] and [[PER2|''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.<ref name=":6" /> Studies on [[thermoregulation]] of [[ruin lizard]]s and mice have informed some connections between the neural and genetic components of both vertebrates when experiencing induced hypothermic conditions.<ref name="mag" /> 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.

*'''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 [[Hypothermia|hypothermic]] mice is more sensitive to the amount of light in their environment.<ref name="toki" /> Even while fasted, mice in darkened conditions and experiencing hypothermia maintained a stable internal body temperature.<ref name="toki" /> 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.<ref name="toki">{{cite journal | vauthors = Tokizawa K, Uchida Y, Nagashima K | title = Thermoregulation in the cold changes depending on the time of day and feeding condition: physiological and anatomical analyses of involved circadian mechanisms | journal = Neuroscience | volume = 164 | issue = 3 | pages = 1377–86 | date = December 2009 | pmid = 19703527 | doi = 10.1016/j.neuroscience.2009.08.040 | s2cid = 207246725 }}</ref> 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.<ref name="cas">{{cite journal | vauthors = Casini G, Petrini P, Foà A, Bagnoli P | title = Pattern of organization of primary visual pathways in the European lizard Podarcis sicula Rafinesque | journal = Journal für Hirnforschung | volume = 34 | issue = 3 | pages = 361–74 | date = 1993 | pmid = 7505790 }}</ref> 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.<ref name="abe">{{cite journal | vauthors = Abraham U, Albrecht U, Gwinner E, Brandstätter R | title = Spatial and temporal variation of passer Per2 gene expression in two distinct cell groups of the suprachiasmatic hypothalamus in the house sparrow (Passer domesticus) | journal = The European Journal of Neuroscience | volume = 16 | issue = 3 | pages = 429–36 | date = August 2002 | pmid = 12193185 | doi = 10.1046/j.1460-9568.2002.02102.x | s2cid = 15282323 }}</ref> 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.<ref name="mag"/>

==Other signals from the retina==
[[Image:Circadian rhythm labeled.jpg|thumb|350px|A variation of an [[Arnold Eskin#Eskinogram|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]]:
* 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.<ref name="pmid16221596">{{cite book | vauthors = Giolli RA, Blanks RH, Lui F | title = Neuroanatomy of the Oculomotor System | chapter = The accessory optic system: basic organization with an update on connectivity, neurochemistry, and function | series = Progress in Brain Research | volume = 151 | pages = 407–40 | date = 2006 | pmid = 16221596 | doi = 10.1016/S0079-6123(05)51013-6 | isbn = 9780444516961 | chapter-url = https://escholarship.org/content/qt3v25z604/qt3v25z604.pdf?t=lnpyco }}</ref>
* The ''pretectum'' controls the size of the [[pupil]].

==Genetic Basis of SCN Function==
The SCN is the central circadian pacemaker of [[mammal]]s, serving as the coordinator of mammalian [[circadian rhythm]]s. Neurons in an intact SCN show coordinated circadian rhythms in electrical activity.<ref>{{Cite journal |last=Prosser |first=R. A. |date=February 1998 |title=In vitro circadian rhythms of the mammalian suprachiasmatic nuclei: comparison of multi-unit and single-unit neuronal activity recordings |url=https://pubmed.ncbi.nlm.nih.gov/9486841/ |journal=Journal of Biological Rhythms |volume=13 |issue=1 |pages=30–38 |doi=10.1177/074873098128999899 |issn=0748-7304 |pmid=9486841|s2cid=1498966 }}</ref> Neurons isolated from the SCN have been shown to produce and sustain circadian rhythms ''[[in vitro]]'',<ref>{{Cite journal |last1=Herzog |first1=E. D. |last2=Takahashi |first2=J. S. |last3=Block |first3=G. D. |date=December 1998 |title=Clock controls circadian period in isolated suprachiasmatic nucleus neurons |url=https://pubmed.ncbi.nlm.nih.gov/10196587/ |journal=Nature Neuroscience |volume=1 |issue=8 |pages=708–713 |doi=10.1038/3708 |issn=1097-6256 |pmid=10196587|s2cid=19112613 }}</ref> suggesting that each individual neuron of the SCN can function as an independent circadian oscillator at the cellular level.<ref>{{Cite book |last1=Honma |first1=Sato |last2=Ono |first2=Daisuke |last3=Suzuki |first3=Yohko |last4=Inagaki |first4=Natsuko |last5=Yoshikawa |first5=Tomoko |last6=Nakamura |first6=Wataru |last7=Honma |first7=Ken-Ichi |chapter=Suprachiasmatic nucleus |date=2012 |title=The Neurobiology of Circadian Timing |url=https://pubmed.ncbi.nlm.nih.gov/22877663/#:~:text=The%20suprachiasmatic%20nucleus%20(SCN),,as%20in%20an%20organotypic%20slice. |series=Progress in Brain Research |volume=199 |pages=129–141 |doi=10.1016/B978-0-444-59427-3.00029-0 |issn=1875-7855 |pmid=22877663|isbn=978-0-444-59427-3 }}</ref> 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.<ref>{{Cite journal |last1=Welsh |first1=David K. |last2=Takahashi |first2=Joseph S. |last3=Kay |first3=Steve A. |date=2010 |title=Suprachiasmatic nucleus: cell autonomy and network properties |journal=Annual Review of Physiology |volume=72 |pages=551–577 |doi=10.1146/annurev-physiol-021909-135919 |issn=1545-1585 |pmc=3758475 |pmid=20148688}}</ref>

=== Mammals ===
The SCN functions as a circadian biological clock in vertebrates including teleosts, reptiles, birds, and mammals.<ref>{{Cite journal |last1=Patton |first1=Andrew P. |last2=Hastings |first2=Michael H. |date=2018-08-06 |title=The suprachiasmatic nucleus |journal=Current Biology |volume=28 |issue=15 |pages=R816–R822 |doi=10.1016/j.cub.2018.06.052 |issn=1879-0445 |pmid=30086310|s2cid=51933991 |doi-access=free }}</ref> In mammals, the rhythms produced by the SCN are driven by a [[Transcription translation feedback loop|transcription-translation negative feedback loop (TTFL)]] composed of interacting positive and negative transcriptional [[Feedback|feedback loops]].<ref>{{Cite book |last1=Buhr |first1=Ethan D. |last2=Takahashi |first2=Joseph S. |title=Circadian Clocks |chapter=Molecular Components of the Mammalian Circadian Clock |date=2013 |series=Handbook of Experimental Pharmacology |volume=217 |issue=217 |pages=3–27 |doi=10.1007/978-3-642-25950-0_1 |issn=0171-2004 |pmc=3762864 |pmid=23604473|isbn=978-3-642-25949-4 }}</ref><ref>{{Cite journal |last1=Shearman |first1=Lauren P. |last2=Sriram |first2=Sathyanarayanan |last3=Weaver |first3=David R. |last4=Maywood |first4=Elizabeth S. |last5=Chaves |first5=Inẽs |last6=Zheng |first6=Binhai |last7=Kume |first7=Kazuhiko |last8=Lee |first8=Cheng Chi |last9=Der |first9=Gijsbertus T. J. van |last10=Horst |last11=Hastings |first11=Michael H. |last12=Reppert |first12=Steven M. |date=2000 |title=Interacting Molecular Loops in the Mammalian Circadian Clock |url=https://www.academia.edu/15431872 |journal=Science |volume=288 |issue=5468 |pages=1013–1019 |doi=10.1126/science.288.5468.1013 |pmid=10807566 |bibcode=2000Sci...288.1013S |issn=0036-8075}}</ref><ref name="Reppert 935–941">{{Cite journal |last1=Reppert |first1=Steven M. |last2=Weaver |first2=David R. |date=2002-08-29 |title=Coordination of circadian timing in mammals |url=https://pubmed.ncbi.nlm.nih.gov/12198538/ |journal=Nature |volume=418 |issue=6901 |pages=935–941 |doi=10.1038/nature00965 |issn=0028-0836 |pmid=12198538|bibcode=2002Natur.418..935R |s2cid=4430366 }}</ref> Within the nucleus of an SCN cell, the genes ''Clock'' and ''Bmal1 (mop3)'' encode the [[Basic helix–loop–helix|BHLH]]-[[PAS domain|PAS]] [[transcription factor]]s [[CLOCK]] and [[ARNTL|BMAL1 (MOP3)]], respectively. CLOCK and BMAL1 are positive [[Activator (genetics)|activators]] that form CLOCK-BMAL1 [[Protein dimer|heterodimers]]. These heterodimers then bind to [[E-box]]es upstream of multiple genes, including ''per'' and ''cry'', to enhance and promote their [[Transcription (biology)|transcription]] and eventual [[Translation (biology)|translation]].<ref name=":6">{{Cite journal |last1=Gekakis |first1=N. |last2=Staknis |first2=D. |last3=Nguyen |first3=H. B. |last4=Davis |first4=F. C. |last5=Wilsbacher |first5=L. D. |last6=King |first6=D. P. |last7=Takahashi |first7=J. S. |last8=Weitz |first8=C. J. |date=1998-06-05 |title=Role of the CLOCK protein in the mammalian circadian mechanism |url=https://pubmed.ncbi.nlm.nih.gov/9616112/ |journal=Science |volume=280 |issue=5369 |pages=1564–1569 |doi=10.1126/science.280.5369.1564 |issn=0036-8075 |pmid=9616112|bibcode=1998Sci...280.1564G }}</ref><ref name="Reppert 935–941"/> In mammals, there are three known [[Sequence homology|homologs]] for the ''[[Period (gene)|period]]'' gene in ''[[Drosophila]]'', namely ''[[PER1|per1]]'', ''[[PER2|per2]]'', and ''[[PER3|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 [[Protein phosphorylation|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.<ref>{{Cite journal |last1=Herzog |first1=Erik D. |last2=Hermanstyne |first2=Tracey |last3=Smyllie |first3=Nicola J. |last4=Hastings |first4=Michael H. |date=2017-01-03 |title=Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms |journal=Cold Spring Harbor Perspectives in Biology |volume=9 |issue=1 |pages=a027706 |doi=10.1101/cshperspect.a027706 |issn=1943-0264 |pmc=5204321 |pmid=28049647}}</ref> As a result, PER and CRY function as negative [[repressor]]s 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.<ref>{{Cite journal |last1=Kume |first1=K. |last2=Zylka |first2=M. J. |last3=Sriram |first3=S. |last4=Shearman |first4=L. P. |last5=Weaver |first5=D. R. |last6=Jin |first6=X. |last7=Maywood |first7=E. S. |last8=Hastings |first8=M. H. |last9=Reppert |first9=S. M. |date=1999-07-23 |title=mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop |journal=Cell |volume=98 |issue=2 |pages=193–205 |doi=10.1016/s0092-8674(00)81014-4 |issn=0092-8674 |pmid=10428031|s2cid=15846072 |doi-access=free }}</ref><ref>{{Cite journal |last1=Okamura |first1=H. |last2=Miyake |first2=S. |last3=Sumi |first3=Y. |last4=Yamaguchi |first4=S. |last5=Yasui |first5=A. |last6=Muijtjens |first6=M. |last7=Hoeijmakers |first7=J. H. |last8=van der Horst |first8=G. T. |date=1999-12-24 |title=Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock |url=https://pubmed.ncbi.nlm.nih.gov/10617474/ |journal=Science |volume=286 |issue=5449 |pages=2531–2534 |doi=10.1126/science.286.5449.2531 |issn=0036-8075 |pmid=10617474}}</ref><ref>{{Cite journal |last1=Gao |first1=Peng |last2=Yoo |first2=Seung-Hee |last3=Lee |first3=Kyung-Jong |last4=Rosensweig |first4=Clark |last5=Takahashi |first5=Joseph S. |last6=Chen |first6=Benjamin P. |last7=Green |first7=Carla B. |date=2013-12-06 |title=Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length |journal=The Journal of Biological Chemistry |volume=288 |issue=49 |pages=35277–35286 |doi=10.1074/jbc.M113.509604 |issn=1083-351X |pmc=3853276 |pmid=24158435 |doi-access=free }}</ref><ref name="Reppert 935–941"/><ref>{{Cite journal |last1=Matsumura |first1=Ritsuko |last2=Tsuchiya |first2=Yoshiki |last3=Tokuda |first3=Isao |last4=Matsuo |first4=Takahiro |last5=Sato |first5=Miho |last6=Node |first6=Koichi |last7=Nishida |first7=Eisuke |last8=Akashi |first8=Makoto |date=2014-11-14 |title=The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK) |journal=The Journal of Biological Chemistry |volume=289 |issue=46 |pages=32064–32072 |doi=10.1074/jbc.M114.578278 |issn=1083-351X |pmc=4231683 |pmid=25271155 |doi-access=free }}</ref> 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''.<ref>{{Cite journal |last=Cassone |first=Vincent M. |date=January 2014 |title=Avian circadian organization: a chorus of clocks |journal=Frontiers in Neuroendocrinology |volume=35 |issue=1 |pages=76–88 |doi=10.1016/j.yfrne.2013.10.002 |issn=1095-6808 |pmc=3946898 |pmid=24157655}}</ref>

==Electrophysiology==
Neurons in the SCN fire [[action potential]]s in a 24-hour rhythm, even under constant conditions.<ref name=":0">{{Cite journal |last1=Welsh |first1=David K. |last2=Takahashi |first2=Joseph S. |last3=Kay |first3=Steve A. |date=2010-03-17 |title=Suprachiasmatic Nucleus: Cell Autonomy and Network Properties |journal=Annual Review of Physiology |language=en |volume=72 |issue=1 |pages=551–577 |doi=10.1146/annurev-physiol-021909-135919 |issn=0066-4278 |pmc=3758475 |pmid=20148688}}</ref> 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 in biology|calcium]] and [[Cyclic adenosine monophosphate|cAMP]].<ref name=":0" />  Thus, depolarization of SCN neurons via cAMP and calcium contributes to the magnitude of the rhythmic gene expression in the SCN.<ref name=":0" />

Further, the SCN synchronizes nerve impulses which spread to various [[Parasympathetic nervous system|parasympathetic]] and [[Sympathetic nervous system|sympathetic]] nuclei.<ref name=":1">{{Cite journal |last=Okamura |first=H. |date=2007 |title=Suprachiasmatic Nucleus Clock Time in the Mammalian Circadian System |journal=Cold Spring Harbor Symposia on Quantitative Biology |language=en |volume=72 |issue=1 |pages=551–556 |doi=10.1101/sqb.2007.72.033 |pmid=18419314 |issn=0091-7451|doi-access=free }}</ref> The sympathetic nuclei drive [[glucocorticoid]] output from the [[adrenal gland]] which activates [[PER1|Per1]] in the body cells, thus resetting the circadian cycle of cells in the body.<ref name=":1" /> Without the SCN, rhythms in body cells dampen over time, which may be due to lack of synchrony between cells.<ref name=":0" />

Many SCN neurons are sensitive to light stimulation via the retina.<ref>{{Cite journal |last1=Morin |first1=L.P. |last2=Allen |first2=C.N. |date=2006 |title=The circadian visual system, 2005 |url=https://linkinghub.elsevier.com/retrieve/pii/S0165017305001165 |journal=Brain Research Reviews |language=en |volume=51 |issue=1 |pages=1–60 |doi=10.1016/j.brainresrev.2005.08.003|pmid=16337005 |s2cid=41579061 |url-access=subscription }}</ref> 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.<ref>{{Cite journal |last1=van den Top |first1=M |last2=Buijs |first2=R.M |last3=Ruijter |first3=J.M |last4=Delagrange |first4=P |last5=Spanswick |first5=D |last6=Hermes |first6=M.L.H.J |date=2001 |title=Melatonin generates an outward potassium current in rat suprachiasmatic nucleus neurones in vitro independent of their circadian rhythm |url=https://linkinghub.elsevier.com/retrieve/pii/S0306452201003463 |journal=[[Neuroscience (journal)|Neuroscience]] |language=en |volume=107 |issue=1 |pages=99–108 |doi=10.1016/S0306-4522(01)00346-3|pmid=11744250 |s2cid=12064196 |url-access=subscription }}</ref><ref>{{Cite journal |last1=Yang |first1=Jing |last2=Jin |first2=Hui Juan |last3=Mocaër |first3=Elisabeth |last4=Seguin |first4=Laure |last5=Zhao |first5=Hua |last6=Rusak |first6=Benjamin |date=2016-06-15 |title=Agomelatine affects rat suprachiasmatic nucleus neurons via melatonin and serotonin receptors |url=https://www.sciencedirect.com/science/article/pii/S0024320516302557 |journal=Life Sciences |language=en |volume=155 |pages=147–154 |doi=10.1016/j.lfs.2016.04.035 |pmid=27269050 |issn=0024-3205|url-access=subscription }}</ref> 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.<ref name=":0" />

== Clinical significance ==

=== Irregular sleep-wake rhythm disorder ===
[[Irregular sleep–wake rhythm|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.<ref name=":3" /><ref>{{Cite journal |last1=Zee |first1=Phyllis C. |last2=Vitiello |first2=Michael V. |date=2009-06-01 |title=Circadian Rhythm Sleep Disorder: Irregular Sleep Wake Rhythm |journal=Sleep Medicine Clinics |series=Basics of Circadian Biology and Circadian Rhythm Sleep Disorders |language=en |volume=4 |issue=2 |pages=213–218 |doi=10.1016/j.jsmc.2009.01.009 |pmid=20160950 |pmc=2768129 |issn=1556-407X}}</ref> 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.<ref name=":3" />

=== Major depressive disorder ===
[[Major depressive disorder|Major depressive disorder (MDD)]] has been associated with altered circadian rhythms.<ref name=":13">{{Cite journal |last1=Landgraf |first1=Dominic |last2=Long |first2=Jaimie E. |last3=Proulx |first3=Christophe D. |last4=Barandas |first4=Rita |last5=Malinow |first5=Roberto |last6=Welsh |first6=David K. |date=2016-12-01 |title=Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice |journal=Biological Psychiatry |series=Novel Signaling Mechanisms in Depression |language=en |volume=80 |issue=11 |pages=827–835 |doi=10.1016/j.biopsych.2016.03.1050 |pmid=27113500 |pmc=5102810 |issn=0006-3223}}</ref> 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|Bmal1]]'' expression in the SCN.<ref name=":13" />

=== Alzheimer's disease ===
The functional disruption of the SCN can be observed in early stages of [[Alzheimer's disease|Alzheimer's disease (AD)]].<ref name=":22">{{Cite journal |last1=Weldemichael |first1=Dawit A. |last2=Grossberg |first2=George T. |date=2010-09-02 |title=Circadian Rhythm Disturbances in Patients with Alzheimer's Disease: A Review |journal=International Journal of Alzheimer's Disease |language=en |volume=2010 |pages=e716453 |doi=10.4061/2010/716453 |pmid=20862344 |pmc=2939436 |issn=2090-8024 |doi-access=free }}</ref> 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 [[Circadian rhythm|biological clock]] and body temperature during rest.<ref name=":22" /> 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.<ref name=":22" />

==History==
The idea that the SCN is the main sleep cycle regulator in mammals was proposed by [[Robert Y. Moore|Robert Moore]], who conducted experiments using radioactive [[amino acid]]s to find where the termination of the [[Retinohypothalamic tract|retinohypothalamic projection]] occurs in rodents.<ref name="Klein">{{Cite book |last1=Klein |first1=David C. |url=https://books.google.com/books?id=8fgwFsmTBwgC&dq=suprachiasmatic+nucleus&pg=PR16 |title=Suprachiasmatic Nucleus: The Mind's Clock |last2=Moore |first2=Robert Y. |last3=Reppert |first3=Steven M. |date=1991 |publisher=Oxford University Press |isbn=978-0-19-506250-2 |language=en}}</ref><ref>{{Citation |last=Moore |first=Robert Y. |title=Chapter One - The Suprachiasmatic Nucleus and the Circadian Timing System |date=2013-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780123969712000014 |journal=Progress in Molecular Biology and Translational Science |volume=119 |pages=1–28 |editor-last=Gillette |editor-first=Martha U. |access-date=2023-04-25 |series=Chronobiology: Biological Timing in Health and Disease |publisher=Academic Press |doi=10.1016/B978-0-12-396971-2.00001-4 |pmid=23899592 |language=en|url-access=subscription }}</ref> Early lesioning experiments in mouse, guinea pig, cat, and opossum established how removal of the SCN results in ablation of circadian rhythm in mammals.<ref name="Klein" />

== See also ==
* [[Chronobiology]]
* [[Photosensitive ganglion cell]]
* [[Sense of time]]
* [[Retinohypothalamic tract]]
*[[Shift work sleep disorder]]
*[[Non-24-hour sleep–wake disorder]]

== References ==
{{Reflist|2}}

== External links ==
* [http://thebrain.mcgill.ca/flash/a/a_02/a_02_cr/a_02_cr_vis/a_02_cr_vis.html Diagram at thebrain.mcgill.ca]

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[[Category:Hypothalamus]]
[[Category:Circadian rhythm]]
[[Category:Sleep physiology]]