Circadian rhythm#Disruption

The earliest recorded account of a circadian process is credited to Theophrastus, dating from the 4th century BC, probably provided to him by report of Androsthenes, a ship's captain serving under Alexander the Great. In his book, 'Περὶ φυτῶν ἱστορία', or 'Enquiry into plants', Theophrastus describes a "tree with many leaves like the rose, and that this closes at night, but opens at sunrise, and by noon is completely unfolded; and at evening again it closes by degrees and remains shut at night, and the natives say that it goes to sleep."{{cite web | vauthors = ((Theophrastus, 'Περὶ φυτῶν ἱστορία')) | title = Enquiry into plants and minor works on odours and weather signs, with an English translation by Sir Arthur Hort, bart 1916 | url = https://www.biodiversitylibrary.org/bibliography/27820 | archive-url = https://web.archive.org/web/20220413104526/https://www.biodiversitylibrary.org/bibliography/27820 | archive-date=2022-04-13 }} The tree mentioned by him was much later identified as the tamarind tree by the botanist, H Bretzl, in his book on the botanical findings of the Alexandrian campaigns.{{Cite book | vauthors = Bretzl H |title=Botanische Forschungen des Alexanderzuges | url = https://archive.org/details/b2486903x |location=Leipzig |publisher=Teubner |year=1903}}{{Page needed|date=September 2010}}

The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year.{{cite book| vauthors = Lu GD |title=Celestial Lancets|date=25 October 2002|publisher=Psychology Press|isbn=978-0-7007-1458-2|pages=137–140}}

In 1729, French scientist Jean-Jacques d'Ortous de Mairan conducted the first experiment designed to distinguish an endogenous clock from responses to daily stimuli. He noted that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica persisted, even when the plants were kept in constant darkness.{{Cite journal | vauthors = de Mairan JJ | title=Observation Botanique | journal=Histoire de l'Académie Royale des Sciences | year=1729 | pages=35–36}}{{cite journal | vauthors = Gardner MJ, Hubbard KE, Hotta CT, Dodd AN, Webb AA | title = How plants tell the time | journal = The Biochemical Journal | volume = 397 | issue = 1 | pages = 15–24 | date = July 2006 | pmid = 16761955 | pmc = 1479754 | doi = 10.1042/BJ20060484 }}

In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours.{{cite journal | vauthors = Dijk DJ, von Schantz M | title = Timing and consolidation of human sleep, wakefulness, and performance by a symphony of oscillators | journal = Journal of Biological Rhythms | volume = 20 | issue = 4 | pages = 279–290 | date = August 2005 | pmid = 16077148 | doi = 10.1177/0748730405278292 | s2cid = 13538323 | doi-access = free }} In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature.{{Cite journal | vauthors = Danchin A |title=Important dates 1900–1919 |journal=HKU-Pasteur Research Centre |url=http://www.pasteur.fr/recherche/unites/REG/causeries/dates_1900.html |archive-url=https://web.archive.org/web/20031020031510/http://www.pasteur.fr/recherche/unites/REG/causeries/dates_1900.html |url-status=dead |archive-date=2003-10-20 |access-date=2008-01-12 }}

In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Auguste Forel, Ingeborg Beling, and Oskar Wahl conducted numerous experiments to determine whether this rhythm was attributable to an endogenous clock.{{cite journal | vauthors = Antle MC, Silver R | title = Neural basis of timing and anticipatory behaviors | journal = The European Journal of Neuroscience | volume = 30 | issue = 9 | pages = 1643–1649 | date = November 2009 | pmid = 19878281 | pmc = 2929840 | doi = 10.1111/j.1460-9568.2009.06959.x }} The existence of circadian rhythm was independently discovered in fruit flies in 1935 by two German zoologists, Hans Kalmus and Erwin Bünning.{{cite journal| vauthors = Bruce VG, Pittendrigh CS |title=Endogenous Rhythms in Insects and Microorganisms|journal=The American Naturalist|date=1957|volume=91|issue=858|pages=179–195|doi=10.1086/281977|bibcode=1957ANat...91..179B |s2cid=83886607}}{{cite journal | vauthors = Pittendrigh CS | title = Temporal organization: reflections of a Darwinian clock-watcher | journal = Annual Review of Physiology | volume = 55 | issue = 1 | pages = 16–54 | date = 1993 | pmid = 8466172 | doi = 10.1146/annurev.ph.55.030193.000313 | s2cid = 45054898 }}

In 1954, an important experiment reported by Colin Pittendrigh demonstrated that eclosion (the process of pupa turning into adult) in Drosophila pseudoobscura was a circadian behaviour. He demonstrated that while temperature played a vital role in eclosion rhythm, the period of eclosion was delayed but not stopped when temperature was decreased.{{cite journal | vauthors = Pittendrigh CS | title = On Temperature Independence in the Clock System Controlling Emergence Time in Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 40 | issue = 10 | pages = 1018–1029 | date = October 1954 | pmid = 16589583 | pmc = 534216 | doi = 10.1073/pnas.40.10.1018 | doi-access = free | bibcode = 1954PNAS...40.1018P }}

The term circadian was coined by Franz Halberg in 1959.{{cite journal | vauthors = Halberg F, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg F, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Frederico P, Siggelova J | title = Transdisciplinary unifying implications of circadian findings in the 1950s | journal = Journal of Circadian Rhythms | volume = 1 | issue = 1 | pages = 2 | date = October 2003 | pmid = 14728726 | pmc = 317388 | doi = 10.1186/1740-3391-1-2 | quote = Eventually I reverted, for the same reason, to "circadian" ... | doi-access = free }} According to Halberg's original definition:

{{Blockquote|The term "circadian" was derived from circa (about) and dies (day); it may serve to imply that certain physiologic periods are close to 24 hours, if not exactly that length. Herein, "circadian" might be applied to all "24-hour" rhythms, whether or not their periods, individually or on the average, are different from 24 hours, longer or shorter, by a few minutes or hours.{{cite journal | vauthors = Halberg F | title = [Physiologic 24-hour periodicity; general and procedural considerations with reference to the adrenal cycle] | journal = Internationale Zeitschrift für Vitaminforschung. Beiheft | volume = 10 | pages = 225–296 | date = 1959 | pmid = 14398945 }}{{cite book| vauthors = Koukkari WL, Sothern RB |title=Introducing Biological Rhythms: A Primer on the Temporal Organization of Life, with Implications for Health, Society, Reproduction, and the Natural Environment|date=2006|publisher=Springer|location=New York|isbn=978-1-4020-3691-0|page=23|url=https://books.google.com/books?id=jQWVfKcdct8C}}}}

In 1977, the International Committee on Nomenclature of the International Society for Chronobiology formally adopted the definition:

{{Blockquote|Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 ± 4 h; circa (about, approximately) and dies (day or 24 h). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods of slightly yet consistently different from 24-h.{{cite journal | vauthors = Halberg F, Carandente F, Cornelissen G, Katinas GS | title = [Glossary of chronobiology (author's transl)] | journal = Chronobiologia | volume = 4 | issue = Suppl 1 | pages = 1–189 | date = 1977 | pmid = 352650 }}}}

Ron Konopka and Seymour Benzer identified the first clock mutation in Drosophila in 1971, naming the gene "period" (per) gene, the first discovered genetic determinant of behavioral rhythmicity.{{cite journal | vauthors = Konopka RJ, Benzer S | title = Clock mutants of Drosophila melanogaster | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 9 | pages = 2112–2116 | date = September 1971 | pmid = 5002428 | pmc = 389363 | doi = 10.1073/pnas.68.9.2112 | doi-access = free | bibcode = 1971PNAS...68.2112K }} The per gene was isolated in 1984 by two teams of researchers. Konopka, Jeffrey Hall, Michael Roshbash and their team showed that per locus is the centre of the circadian rhythm, and that loss of per stops circadian activity.{{cite journal | vauthors = Reddy P, Zehring WA, Wheeler DA, Pirrotta V, Hadfield C, Hall JC, Rosbash M | title = Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms | journal = Cell | volume = 38 | issue = 3 | pages = 701–710 | date = October 1984 | pmid = 6435882 | doi = 10.1016/0092-8674(84)90265-4 | s2cid = 316424 }}{{cite journal | vauthors = Zehring WA, Wheeler DA, Reddy P, Konopka RJ, Kyriacou CP, Rosbash M, Hall JC | title = P-element transformation with period locus DNA restores rhythmicity to mutant, arrhythmic Drosophila melanogaster | journal = Cell | volume = 39 | issue = 2 Pt 1 | pages = 369–376 | date = December 1984 | pmid = 6094014 | doi = 10.1016/0092-8674(84)90015-1 | doi-access = free }} At the same time, Michael W. Young's team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA.{{cite journal | vauthors = Bargiello TA, Jackson FR, Young MW | title = Restoration of circadian behavioural rhythms by gene transfer in Drosophila | journal = Nature | volume = 312 | issue = 5996 | pages = 752–754 | date = 1984 | pmid = 6440029 | doi = 10.1038/312752a0 | s2cid = 4259316 | bibcode = 1984Natur.312..752B }}{{cite journal | vauthors = Bargiello TA, Young MW | title = Molecular genetics of a biological clock in Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 7 | pages = 2142–2146 | date = April 1984 | pmid = 16593450 | pmc = 345453 | doi = 10.1038/312752a0 | bibcode = 1984Natur.312..752B }} They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017.{{Cite web|title=The Nobel Prize in Physiology or Medicine 2017|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/|access-date=2017-10-06|website=www.nobelprize.org}}

Joseph Takahashi discovered the first mammalian circadian clock mutation (clockΔ19) using mice in 1994.{{MEDRS|date=November 2013}} {{Cite news |title=Gene Discovered in Mice that Regulates Biological Clock |work=Chicago Tribune |date=29 April 1994}}{{primary source inline|date=November 2013}} {{cite journal | vauthors = Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS | title = Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior | journal = Science | volume = 264 | issue = 5159 | pages = 719–725 | date = April 1994 | pmid = 8171325 | pmc = 3839659 | doi = 10.1126/science.8171325 | bibcode = 1994Sci...264..719H }} However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation.{{cite journal | vauthors = Debruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM | title = A clock shock: mouse CLOCK is not required for circadian oscillator function | journal = Neuron | volume = 50 | issue = 3 | pages = 465–477 | date = May 2006 | pmid = 16675400 | doi = 10.1016/j.neuron.2006.03.041 | s2cid = 19028601 | doi-access = free }}{{cite journal | vauthors = Collins B, Blau J | title = Keeping time without a clock | journal = Neuron | volume = 50 | issue = 3 | pages = 348–350 | date = May 2006 | pmid = 16675389 | doi = 10.1016/j.neuron.2006.04.022 | doi-access = free }}

The first human clock mutation was identified in an extended Utah family by Chris Jones, and genetically characterized by Ying-Hui Fu and Louis Ptacek. Affected individuals are extreme 'morning larks' with 4-hour advanced sleep and other rhythms. This form of familial advanced sleep phase syndrome is caused by a single amino acid change, S662➔G, in the human PER2 protein.{{cite journal | vauthors = Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH | title = An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome | journal = Science | volume = 291 | issue = 5506 | pages = 1040–1043 | date = February 2001 | pmid = 11232563 | doi = 10.1126/science.1057499 | s2cid = 1848310 | bibcode = 2001Sci...291.1040T }}{{cite journal | vauthors = Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, Murphy PJ, Jones B, Czajkowski L, Ptácek LJ | title = Familial advanced sleep-phase syndrome: A short-period circadian rhythm variant in humans | journal = Nature Medicine | volume = 5 | issue = 9 | pages = 1062–1065 | date = September 1999 | pmid = 10470086 | doi = 10.1038/12502 | s2cid = 14809619 }}

To be called circadian, a biological rhythm must meet these three general criteria:{{cite book| vauthors = Johnson C |title=Chronobiology: Biological Timekeeping|year=2004|publisher=Sinauer Associates, Inc.|location=Sunderland, Massachusetts, USA|pages=67–105}}

1. The rhythm has an endogenously derived free-running period of time that lasts approximately 24 hours. The rhythm persists in constant conditions, i.e. constant darkness, with a period of about 24 hours. The period of the rhythm in constant conditions is called the free-running period and is denoted by the Greek letter τ (tau). The rationale for this criterion is to distinguish circadian rhythms from simple responses to daily external cues. A rhythm cannot be said to be endogenous unless it has been tested and persists in conditions without external periodic input. In diurnal animals (active during daylight hours), in general τ is slightly greater than 24 hours, whereas, in nocturnal animals (active at night), in general τ is shorter than 24 hours.{{Citation needed|date=November 2024}}
2. The rhythms are entrainable. The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment. The external stimulus used to entrain a rhythm is called the zeitgeber, or "time giver". Travel across time zones illustrates the ability of the human biological clock to adjust to the local time; a person will usually experience jet lag before entrainment of their circadian clock has brought it into sync with local time.
3. The rhythms exhibit temperature compensation. In other words, they maintain circadian periodicity over a range of physiological temperatures. Many organisms live at a broad range of temperatures, and differences in thermal energy will affect the kinetics of all molecular processes in their {{Not a typo|cell(s)}}. In order to keep track of time, the organism's circadian clock must maintain roughly a 24-hour periodicity despite the changing kinetics, a property known as temperature compensation. The Q₁₀ temperature coefficient is a measure of this compensating effect. If the Q₁₀ coefficient remains approximately 1 as temperature increases, the rhythm is considered to be temperature-compensated.

{{missing information|section|independently evolved four times [PMID 11533719]|date=September 2021}}

Circadian rhythms allow organisms to anticipate and prepare for precise and regular environmental changes. They thus enable organisms to make better use of environmental resources (e.g. light and food) compared to those that cannot predict such availability. It has therefore been suggested that circadian rhythms put organisms at a selective advantage in evolutionary terms. However, rhythmicity appears to be as important in regulating and coordinating internal metabolic processes, as in coordinating with the environment.{{cite journal | vauthors = Sharma VK | title = Adaptive significance of circadian clocks | journal = Chronobiology International | volume = 20 | issue = 6 | pages = 901–919 | date = November 2003 | pmid = 14680135 | doi = 10.1081/CBI-120026099 | s2cid = 10899279 }} This is suggested by the maintenance (heritability) of circadian rhythms in fruit flies after several hundred generations in constant laboratory conditions,{{primary source inline|date=November 2013}} {{cite journal | vauthors = Sheeba V, Sharma VK, Chandrashekaran MK, Joshi A | title = Persistence of eclosion rhythm in Drosophila melanogaster after 600 generations in an aperiodic environment | journal = Die Naturwissenschaften | volume = 86 | issue = 9 | pages = 448–449 | date = September 1999 | pmid = 10501695 | doi = 10.1007/s001140050651 | s2cid = 13401297 | bibcode = 1999NW.....86..448S }} as well as in creatures in constant darkness in the wild, and by the experimental elimination of behavioral—but not physiological—circadian rhythms in quail.{{primary source inline|date=November 2013}} {{cite journal | vauthors = Guyomarc'h C, Lumineau S, Richard JP | title = Circadian rhythm of activity in Japanese quail in constant darkness: variability of clarity and possibility of selection | journal = Chronobiology International | volume = 15 | issue = 3 | pages = 219–230 | date = May 1998 | pmid = 9653576 | doi = 10.3109/07420529808998685 }}{{primary source inline|date=November 2013}} {{cite journal | vauthors = Zivkovic BD, Underwood H, Steele CT, Edmonds K | title = Formal properties of the circadian and photoperiodic systems of Japanese quail: phase response curve and effects of T-cycles | journal = Journal of Biological Rhythms | volume = 14 | issue = 5 | pages = 378–390 | date = October 1999 | pmid = 10511005 | doi = 10.1177/074873099129000786 | s2cid = 13390422 | doi-access = free }}

What drove circadian rhythms to evolve has been an enigmatic question. Previous hypotheses emphasized that photosensitive proteins and circadian rhythms may have originated together in the earliest cells, with the purpose of protecting replicating DNA from high levels of damaging ultraviolet radiation during the daytime. As a result, replication was relegated to the dark. However, evidence for this is lacking: in fact the simplest organisms with a circadian rhythm, the cyanobacteria, do the opposite of this: they divide more in the daytime.{{cite journal | vauthors = Mori T, Johnson CH | title = Independence of circadian timing from cell division in cyanobacteria | journal = Journal of Bacteriology | volume = 183 | issue = 8 | pages = 2439–2444 | date = April 2001 | pmid = 11274102 | pmc = 95159 | doi = 10.1128/JB.183.8.2439-2444.2001 }} Recent studies instead highlight the importance of co-evolution of redox proteins with circadian oscillators in all three domains of life following the Great Oxidation Event approximately 2.3 billion years ago. The current view is that circadian changes in environmental oxygen levels and the production of reactive oxygen species (ROS) in the presence of daylight are likely to have driven a need to evolve circadian rhythms to preempt, and therefore counteract, damaging redox reactions on a daily basis.

The simplest known circadian clocks are bacterial circadian rhythms, exemplified by the prokaryote cyanobacteria. Recent research has demonstrated that the circadian clock of Synechococcus elongatus can be reconstituted in vitro with just the three proteins (KaiA, KaiB, KaiC){{cite journal | vauthors = Hut RA, Beersma DG | title = Evolution of time-keeping mechanisms: early emergence and adaptation to photoperiod | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 366 | issue = 1574 | pages = 2141–2154 | date = July 2011 | pmid = 21690131 | pmc = 3130368 | doi = 10.1098/rstb.2010.0409 }} of their central oscillator. This clock has been shown to sustain a 22-hour rhythm over several days upon the addition of ATP. Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription/translation feedback mechanism.{{citation needed|date=November 2013}}

A defect in the human homologue of the Drosophila "period" gene was identified as a cause of the sleep disorder FASPS (Familial advanced sleep phase syndrome), underscoring the conserved nature of the molecular circadian clock through evolution. Many more genetic components of the biological clock are now known. Their interactions result in an interlocked feedback loop of gene products resulting in periodic fluctuations that the cells of the body interpret as a specific time of the day.{{cite journal | vauthors = Dubowy C, Sehgal A | title = Circadian Rhythms and Sleep in Drosophila melanogaster | journal = Genetics | volume = 205 | issue = 4 | pages = 1373–1397 | date = April 2017 | pmid = 28360128 | pmc = 5378101 | doi = 10.1534/genetics.115.185157 }}

It is now known that the molecular circadian clock can function within a single cell. That is, it is cell-autonomous.{{MEDRS|date=November 2013}} {{cite journal | vauthors = Nagoshi E, Saini C, Bauer C, Laroche T, Naef F, Schibler U | title = Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells | journal = Cell | volume = 119 | issue = 5 | pages = 693–705 | date = November 2004 | pmid = 15550250 | doi = 10.1016/j.cell.2004.11.015 | s2cid = 15633902 | doi-access = free }} This was shown by Gene Block in isolated mollusk basal retinal neurons (BRNs).{{primary source inline|date=November 2013}} {{cite journal | vauthors = Michel S, Geusz ME, Zaritsky JJ, Block GD | title = Circadian rhythm in membrane conductance expressed in isolated neurons | journal = Science | volume = 259 | issue = 5092 | pages = 239–241 | date = January 1993 | pmid = 8421785 | doi = 10.1126/science.8421785 | bibcode = 1993Sci...259..239M | url = https://zenodo.org/record/1231259 }} At the same time, different cells may communicate with each other resulting in a synchronized output of electrical signaling. These may interface with endocrine glands of the brain to result in periodic release of hormones. The receptors for these hormones may be located far across the body and synchronize the peripheral clocks of various organs. Thus, the information of the time of the day as relayed by the eyes travels to the clock in the brain, and, through that, clocks in the rest of the body may be synchronized. This is how the timing of, for example, sleep/wake, body temperature, thirst, and appetite are coordinately controlled by the biological clock.{{cite journal | vauthors = Refinetti R | title = The circadian rhythm of body temperature | journal = Frontiers in Bioscience | volume = 15 | issue = 2 | pages = 564–594 | date = January 2010 | pmid = 20036834 | doi = 10.2741/3634 | s2cid = 36170900 | doi-access = free }}{{cite journal | vauthors = Scheer FA, Morris CJ, Shea SA | title = The internal circadian clock increases hunger and appetite in the evening independent of food intake and other behaviors | journal = Obesity | volume = 21 | issue = 3 | pages = 421–423 | date = March 2013 | pmid = 23456944 | pmc = 3655529 | doi = 10.1002/oby.20351 }}

Circadian rhythmicity is present in the sleeping and feeding patterns of animals, including human beings. There are also clear patterns of core body temperature, brain wave activity, hormone production, cell regeneration, and other biological activities. In addition, photoperiodism, the physiological reaction of organisms to the length of day or night, is vital to both plants and animals, and the circadian system plays a role in the measurement and interpretation of day length. Timely prediction of seasonal periods of weather conditions, food availability, or predator activity is crucial for survival of many species. Although not the only parameter, the changing length of the photoperiod (day length) is the most predictive environmental cue for the seasonal timing of physiology and behavior, most notably for timing of migration, hibernation, and reproduction.{{MEDRS|date=November 2013}} {{cite web |title=Clock Tutorial #16: Photoperiodism – Models and Experimental Approaches (original work from 2005-08-13) |url=http://scienceblogs.com/clock/2007/07/clock_tutorial_16_photoperiodi_1.php |access-date=2007-12-09 | vauthors = Zivkovic BC |date=2007-07-25 |work=A Blog Around the Clock |publisher=ScienceBlogs |archive-url= https://web.archive.org/web/20080101142300/http://scienceblogs.com/clock/2007/07/clock_tutorial_16_photoperiodi_1.php |archive-date=2008-01-01 |url-status=dead }}

Mutations or deletions of clock genes in mice have demonstrated the importance of body clocks to ensure the proper timing of cellular/metabolic events; clock-mutant mice are hyperphagic and obese, and have altered glucose metabolism.{{primary source inline|date=December 2013}} {{cite journal | vauthors = Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J | title = Obesity and metabolic syndrome in circadian Clock mutant mice | journal = Science | volume = 308 | issue = 5724 | pages = 1043–1045 | date = May 2005 | pmid = 15845877 | pmc = 3764501 | doi = 10.1126/science.1108750 | bibcode = 2005Sci...308.1043T }} In mice, deletion of the Rev-ErbA alpha clock gene can result in diet-induced obesity and changes the balance between glucose and lipid utilization, predisposing to diabetes.{{cite journal | vauthors = Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, Teboul M, Delaunay F, Pévet P, Challet E | title = The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism | journal = FASEB Journal | volume = 26 | issue = 8 | pages = 3321–3335 | date = August 2012 | pmid = 22562834 | doi = 10.1096/fj.12-208751 | doi-access = free | s2cid = 31204290 }} However, it is not clear whether there is a strong association between clock gene polymorphisms in humans and the susceptibility to develop the metabolic syndrome.{{primary source inline|date=December 2013}} {{cite journal | vauthors = Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, Teboul M, Delaunay F, Pévet P, Challet E | title = The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism | journal = FASEB Journal | volume = 26 | issue = 8 | pages = 3321–3335 | date = August 2012 | pmid = 22562834 | doi = 10.1096/fj.12-208751 | doi-access = free | s2cid = 31204290 }}{{primary source inline|date=December 2013}} {{cite journal | vauthors = Scott EM, Carter AM, Grant PJ | title = Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man | journal = International Journal of Obesity | volume = 32 | issue = 4 | pages = 658–662 | date = April 2008 | pmid = 18071340 | doi = 10.1038/sj.ijo.0803778 | doi-access = free }}

The rhythm is linked to the light–dark cycle. Animals, including humans, kept in total darkness for extended periods eventually function with a free-running rhythm. Their sleep cycle is pushed back or forward each "day", depending on whether their "day", their endogenous period, is shorter or longer than 24 hours. The environmental cues that reset the rhythms each day are called zeitgebers.{{MEDRS|date=November 2013}} {{cite web |vauthors=Shneerson JM, Ohayon MM, Carskadon MA |title=Circadian rhythms |publisher=Armenian Medical Network |work=Rapid eye movement (REM) sleep |url=http://www.sleep.health.am/sleep/more/circadian-rhythms/ |year=2007 |access-date=2007-09-19 |archive-date=2007-10-14 |archive-url=https://web.archive.org/web/20071014050810/http://www.sleep.health.am/sleep/more/circadian-rhythms/ |url-status=dead }} Totally blind subterranean mammals (e.g., blind mole rat Spalax sp.) are able to maintain their endogenous clocks in the apparent absence of external stimuli. Although they lack image-forming eyes, their photoreceptors (which detect light) are still functional; they do surface periodically as well.{{page needed|date=November 2013}}"The Rhythms of Life: The Biological Clocks That Control the Daily Lives of Every Living Thing" Russell Foster & Leon Kreitzman, Publisher: Profile Books Ltd.

Free-running organisms that normally have one or two consolidated sleep episodes will still have them when in an environment shielded from external cues, but the rhythm is not entrained to the 24-hour light–dark cycle in nature. The sleep–wake rhythm may, in these circumstances, become out of phase with other circadian or ultradian rhythms such as metabolic, hormonal, CNS electrical, or neurotransmitter rhythms.{{MEDRS|date=November 2013}} {{cite journal | vauthors = Regestein QR, Pavlova M | title = Treatment of delayed sleep phase syndrome | journal = General Hospital Psychiatry | volume = 17 | issue = 5 | pages = 335–345 | date = September 1995 | pmid = 8522148 | doi = 10.1016/0163-8343(95)00062-V }}

Recent research has influenced the design of spacecraft environments, as systems that mimic the light–dark cycle have been found to be highly beneficial to astronauts.{{MEDRS|date=November 2013}}{{cite web | url=http://www.space.com/18917-astronauts-insomnia-light-bulbs.html | vauthors = Howell E | title=Space Station to Get New Insomnia-Fighting Light Bulbs | website = Space.com | date=14 December 2012 | access-date=2012-12-17}} Light therapy has been trialed as a treatment for sleep disorders.

Norwegian researchers at the University of Tromsø have shown that some Arctic animals (e.g., ptarmigan, reindeer) show circadian rhythms only in the parts of the year that have daily sunrises and sunsets. In one study of reindeer, animals at 70 degrees North showed circadian rhythms in the autumn, winter and spring, but not in the summer. Reindeer on Svalbard at 78 degrees North showed such rhythms only in autumn and spring. The researchers suspect that other Arctic animals as well may not show circadian rhythms in the constant light of summer and the constant dark of winter.{{primary source inline|date=November 2013}} {{Cite news | vauthors = Spilde I |title=Reinsdyr uten døgnrytme |url=http://www.forskning.no/Artikler/2005/desember/1135264557.29 |publisher=forskning.no |date=December 2005 |access-date=2007-11-24 |language=nb |quote=...så det ikke ut til at reinen hadde noen døgnrytme om sommeren. Svalbardreinen hadde det heller ikke om vinteren. |archive-url=https://web.archive.org/web/20071203214441/http://www.forskning.no/Artikler/2005/desember/1135264557.29 |archive-date=2007-12-03 |url-status=dead }}

A 2006 study in northern Alaska found that day-living ground squirrels and nocturnal porcupines strictly maintain their circadian rhythms through 82 days and nights of sunshine. The researchers speculate that these two rodents notice that the apparent distance between the sun and the horizon is shortest once a day, and thus have a sufficient signal to entrain (adjust) by.{{cite journal |title=Mammalian activity – rest rhythms in Arctic continuous daylight |journal=Biological Rhythm Research |date=2006-12-01 | vauthors = Folk GE, Thrift DL, Zimmerman MB, Reimann P |s2cid=84625255 |volume=37 |issue=6 |pages=455–469 |doi=10.1080/09291010600738551 |bibcode=2006BioRR..37..455F |quote=Would local animals maintained under natural continuous daylight demonstrate the Aschoff effect described in previously published laboratory experiments using continuous light, in which rats' circadian activity patterns changed systematically to a longer period, expressing a 26-hour day of activity and rest? }}

The navigation of the fall migration of the Eastern North American monarch butterfly (Danaus plexippus) to their overwintering grounds in central Mexico uses a time-compensated sun compass that depends upon a circadian clock in their antennae.{{primary source inline|date=November 2013}} {{cite journal | vauthors = Merlin C, Gegear RJ, Reppert SM | title = Antennal circadian clocks coordinate sun compass orientation in migratory monarch butterflies | journal = Science | volume = 325 | issue = 5948 | pages = 1700–1704 | date = September 2009 | pmid = 19779201 | pmc = 2754321 | doi = 10.1126/science.1176221 | bibcode = 2009Sci...325.1700M }}{{primary source inline|date=November 2013}} {{cite journal | vauthors = Kyriacou CP | title = Physiology. Unraveling traveling | journal = Science | volume = 325 | issue = 5948 | pages = 1629–1630 | date = September 2009 | pmid = 19779177 | doi = 10.1126/science.1178935 | s2cid = 206522416 }} Circadian rhythm is also known to control mating behavioral in certain moth species such as Spodoptera littoralis, where females produce specific pheromone that attracts and resets the male circadian rhythm to induce mating at night.{{cite journal | vauthors = Silvegren G, Löfstedt C, Qi Rosén W | title = Circadian mating activity and effect of pheromone pre-exposure on pheromone response rhythms in the moth Spodoptera littoralis | journal = Journal of Insect Physiology | volume = 51 | issue = 3 | pages = 277–286 | date = March 2005 | pmid = 15749110 | doi = 10.1016/j.jinsphys.2004.11.013 | bibcode = 2005JInsP..51..277S }}

Although light is the primary synchronizer of the circadian rhythm through the suprachiasmatic nucleus (SCN), other environmental signals also influence the biological clock. Feeding plays a key role in regulating peripheral clocks found in the liver, muscles, and adipose tissues. Time-restricted feeding can adjust these clocks by modifying light signals. Additionally, physical activity affects the circadian phase, notably by adjusting melatonin production and body temperature. Temperature itself is an important synchronizer, capable of modifying cellular circadian rhythms. Finally, stress and the release of glucocorticoids influence the expression of clock genes, potentially disrupting biological cycles. Integrating these factors is essential for understanding circadian rhythms beyond simple light regulation.{{Cite journal |last1=Takahashi |first1=Joseph S. |year=2017 |title=Transcriptional architecture of the mammalian circadian clock |journal=Nature Reviews Genetics |volume=18 |issue=3 |pages=164–179 |doi=10.1038/nrg.2016.150 |pmc=5501165 |pmid=27990019}}

File:Jungpflanze des Seidenbaums (Schlafbaum).png

Plant circadian rhythms tell the plant what season it is and when to flower for the best chance of attracting pollinators. Behaviors showing rhythms include leaf movement (Nyctinasty), growth, germination, stomatal/gas exchange, enzyme activity, photosynthetic activity, and fragrance emission, among others.{{cite journal | vauthors = Webb AA | title = The physiology of circadian rhythms in plants | journal = The New Phytologist | volume = 160 | issue = 2 | pages = 281–303 | date = November 2003 | pmid = 33832173 | doi = 10.1046/j.1469-8137.2003.00895.x | s2cid = 15688409 | jstor = 1514280 | doi-access = free | bibcode = 2003NewPh.160..281W }} Circadian rhythms occur as a plant entrains to synchronize with the light cycle of its surrounding environment. These rhythms are endogenously generated, self-sustaining and are relatively constant over a range of ambient temperatures. Important features include two interacting transcription-translation feedback loops: proteins containing PAS domains, which facilitate protein-protein interactions; and several photoreceptors that fine-tune the clock to different light conditions. Anticipation of changes in the environment allows appropriate changes in a plant's physiological state, conferring an adaptive advantage.{{cite journal | vauthors = McClung CR | title = Plant circadian rhythms | journal = The Plant Cell | volume = 18 | issue = 4 | pages = 792–803 | date = April 2006 | pmid = 16595397 | pmc = 1425852 | doi = 10.1105/tpc.106.040980 | bibcode = 2006PlanC..18..792M }} A better understanding of plant circadian rhythms has applications in agriculture, such as helping farmers stagger crop harvests to extend crop availability and securing against massive losses due to weather.

Light is the signal by which plants synchronize their internal clocks to their environment and is sensed by a wide variety of photoreceptors. Red and blue light are absorbed through several phytochromes and cryptochromes. Phytochrome A, phyA, is light labile and allows germination and de-etiolation when light is scarce.{{cite journal | vauthors = Legris M, Ince YÇ, Fankhauser C | title = Molecular mechanisms underlying phytochrome-controlled morphogenesis in plants | journal = Nature Communications | volume = 10 | issue = 1 | pages = 5219 | date = November 2019 | pmid = 31745087 | pmc = 6864062 | doi = 10.1038/s41467-019-13045-0 | bibcode = 2019NatCo..10.5219L }} Phytochromes B–E are more stable with {{Not a typo|phyB}}, the main phytochrome in seedlings grown in the light. The cryptochrome (cry) gene is also a light-sensitive component of the circadian clock and is thought to be involved both as a photoreceptor and as part of the clock's endogenous pacemaker mechanism. Cryptochromes 1–2 (involved in blue–UVA) help to maintain the period length in the clock through a whole range of light conditions.

File:Data on circadian rhythm of gene expression in four seedlings. Two of these Arabidopsis thaliana seedlings carry a firefly luciferase reporter for transcription of the gene CCA1 and two for TOC1.png of circadian reporter genes. Transgenic seedlings of Arabidopsis thaliana were imaged by a cooled CCD camera under three cycles of 12h light: 12h dark followed by 3 days of constant light (from 96h). Their genomes carry firefly luciferase reporter genes driven by the promoter sequences of clock genes. The signals of seedlings 61 (red) and 62 (blue) reflect transcription of the gene CCA1, peaking after lights-on (48h, 72h, etc.). Seedlings 64 (pale grey) and 65 (teal) reflect TOC1, peaking before lights-off (36h, 60h, etc.). The timeseries show 24-hour, circadian rhythms of gene expression in the living plants.]]

The central oscillator generates a self-sustaining rhythm and is driven by two interacting feedback loops that are active at different times of day. The morning loop consists of CCA1 (Circadian and Clock-Associated 1) and LHY (Late Elongated Hypocotyl), which encode closely related MYB transcription factors that regulate circadian rhythms in Arabidopsis, as well as PRR 7 and 9 (Pseudo-Response Regulators.) The evening loop consists of GI (Gigantea) and ELF4, both involved in regulation of flowering time genes.{{cite journal | vauthors = Mizoguchi T, Wright L, Fujiwara S, Cremer F, Lee K, Onouchi H, Mouradov A, Fowler S, Kamada H, Putterill J, Coupland G | title = Distinct roles of GIGANTEA in promoting flowering and regulating circadian rhythms in Arabidopsis | journal = The Plant Cell | volume = 17 | issue = 8 | pages = 2255–2270 | date = August 2005 | pmid = 16006578 | pmc = 1182487 | doi = 10.1105/tpc.105.033464 | bibcode = 2005PlanC..17.2255M }}{{cite journal | vauthors = Kolmos E, Davis SJ | title = ELF4 as a Central Gene in the Circadian Clock | journal = Plant Signaling & Behavior | volume = 2 | issue = 5 | pages = 370–372 | date = September 2007 | pmid = 19704602 | pmc = 2634215 | doi = 10.4161/psb.2.5.4463 | bibcode = 2007PlSiB...2..370K }} When CCA1 and LHY are overexpressed (under constant light or dark conditions), plants become arrhythmic, and mRNA signals reduce, contributing to a negative feedback loop. Gene expression of CCA1 and LHY oscillates and peaks in the early morning, whereas TOC1 gene expression oscillates and peaks in the early evening. While it was previously hypothesised that these three genes model a negative feedback loop in which over-expressed CCA1 and LHY repress TOC1 and over-expressed TOC1 is a positive regulator of CCA1 and LHY, it was shown in 2012 by Andrew Millar and others that TOC1, in fact, serves as a repressor not only of CCA1, LHY, and PRR7 and 9 in the morning loop but also of GI and ELF4 in the evening loop. This finding and further computational modeling of TOC1 gene functions and interactions suggest a reframing of the plant circadian clock as a triple negative-component repressilator model rather than the positive/negative-element feedback loop characterizing the clock in mammals.{{cite journal | vauthors = Pokhilko A, Fernández AP, Edwards KD, Southern MM, Halliday KJ, Millar AJ | title = The clock gene circuit in Arabidopsis includes a repressilator with additional feedback loops | journal = Molecular Systems Biology | volume = 8 | pages = 574 | date = March 2012 | pmid = 22395476 | pmc = 3321525 | doi = 10.1038/msb.2012.6 }}

In 2018, researchers found that the expression of PRR5 and TOC1 hnRNA nascent transcripts follows the same oscillatory pattern as processed mRNA transcripts rhythmically in A. thaliana. LNKs binds to the 5'region of PRR5 and TOC1 and interacts with RNAP II and other transcription factors. Moreover, RVE8-LNKs interaction enables a permissive histone-methylation pattern (H3K4me3) to be modified and the histone-modification itself parallels the oscillation of clock gene expression.{{cite journal | vauthors = Ma Y, Gil S, Grasser KD, Mas P | title = Targeted Recruitment of the Basal Transcriptional Machinery by LNK Clock Components Controls the Circadian Rhythms of Nascent RNAs in Arabidopsis | journal = The Plant Cell | volume = 30 | issue = 4 | pages = 907–924 | date = April 2018 | pmid = 29618629 | pmc = 5973845 | doi = 10.1105/tpc.18.00052 | bibcode = 2018PlanC..30..907M }}

It has previously been found that matching a plant's circadian rhythm to its external environment's light and dark cycles has the potential to positively affect the plant.{{cite journal | vauthors = Dodd AN, Salathia N, Hall A, Kévei E, Tóth R, Nagy F, Hibberd JM, Millar AJ, Webb AA | title = Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage | journal = Science | volume = 309 | issue = 5734 | pages = 630–633 | date = July 2005 | pmid = 16040710 | doi = 10.1126/science.1115581 | s2cid = 25739247 | bibcode = 2005Sci...309..630D }} Researchers came to this conclusion by performing experiments on three different varieties of Arabidopsis thaliana. One of these varieties had a normal 24-hour circadian cycle. The other two varieties were mutated, one to have a circadian cycle of more than 27 hours, and one to have a shorter than normal circadian cycle of 20 hours.

The Arabidopsis with the 24-hour circadian cycle was grown in three different environments. One of these environments had a 20-hour light and dark cycle (10 hours of light and 10 hours of dark), the other had a 24-hour light and dark cycle (12 hours of light and 12 hours of dark),and the final environment had a 28-hour light and dark cycle (14 hours of light and 14 hours of dark). The two mutated plants were grown in both an environment that had a 20-hour light and dark cycle and in an environment that had a 28-hour light and dark cycle. It was found that the variety of Arabidopsis with a 24-hour circadian rhythm cycle grew best in an environment that also had a 24-hour light and dark cycle. Overall, it was found that all the varieties of Arabidopsis thaliana had greater levels of chlorophyll and increased growth in environments whose light and dark cycles matched their circadian rhythm.

Researchers suggested that a reason for this could be that matching an Arabidopsis{{'s}} circadian rhythm to its environment could allow the plant to be better prepared for dawn and dusk, and thus be able to better synchronize its processes. In this study, it was also found that the genes that help to control chlorophyll peaked a few hours after dawn. This appears to be consistent with the proposed phenomenon known as metabolic dawn.{{cite journal | vauthors = Dodd AN, Belbin FE, Frank A, Webb AA | title = Interactions between circadian clocks and photosynthesis for the temporal and spatial coordination of metabolism | journal = Frontiers in Plant Science | volume = 6 | pages = 245 | year = 2015 | pmid = 25914715 | pmc = 4391236 | doi = 10.3389/fpls.2015.00245 | doi-access = free }}

According to the metabolic dawn hypothesis, sugars produced by photosynthesis have potential to help regulate the circadian rhythm and certain photosynthetic and metabolic pathways.{{cite journal | vauthors = Webb AA, Seki M, Satake A, Caldana C | title = Continuous dynamic adjustment of the plant circadian oscillator | journal = Nature Communications | volume = 10 | issue = 1 | pages = 550 | date = February 2019 | pmid = 30710080 | pmc = 6358598 | doi = 10.1038/s41467-019-08398-5 | bibcode = 2019NatCo..10..550W }} As the sun rises, more light becomes available, which normally allows more photosynthesis to occur. The sugars produced by photosynthesis repress PRR7.{{cite journal | vauthors = Haydon MJ, Mielczarek O, Robertson FC, Hubbard KE, Webb AA | title = Photosynthetic entrainment of the Arabidopsis thaliana circadian clock | journal = Nature | volume = 502 | issue = 7473 | pages = 689–692 | date = October 2013 | pmid = 24153186 | pmc = 3827739 | doi = 10.1038/nature12603 | bibcode = 2013Natur.502..689H }} This repression of PRR7 then leads to the increased expression of CCA1. On the other hand, decreased photosynthetic sugar levels increase PRR7 expression and decrease CCA1 expression. This feedback loop between CCA1 and PRR7 is what is proposed to cause metabolic dawn.{{cite journal | vauthors = Farré EM, Kay SA | title = PRR7 protein levels are regulated by light and the circadian clock in Arabidopsis | journal = The Plant Journal | volume = 52 | issue = 3 | pages = 548–560 | date = November 2007 | pmid = 17877705 | doi = 10.1111/j.1365-313X.2007.03258.x | doi-access = free }}

{{Main|Drosophila circadian rhythm}}

File:Drosophila brains and the circadian system.jpg

The molecular mechanism of circadian rhythm and light perception are best understood in Drosophila. Clock genes are discovered from Drosophila, and they act together with the clock neurones. There are two unique rhythms, one during the process of hatching (called eclosion) from the pupa, and the other during mating.{{cite journal | vauthors = Veleri S, Wülbeck C | title = Unique self-sustaining circadian oscillators within the brain of Drosophila melanogaster | journal = Chronobiology International | volume = 21 | issue = 3 | pages = 329–342 | date = May 2004 | pmid = 15332440 | doi = 10.1081/CBI-120038597 | s2cid = 15099796 }} The clock neurones are located in distinct clusters in the central brain. The best-understood clock neurones are the large and small lateral ventral neurons (l-LNvs and s-LNvs) of the optic lobe. These neurones produce pigment dispersing factor (PDF), a neuropeptide that acts as a circadian neuromodulator between different clock neurones.{{cite journal | vauthors = Yoshii T, Hermann-Luibl C, Helfrich-Förster C | title = Circadian light-input pathways in Drosophila | journal = Communicative & Integrative Biology | volume = 9 | issue = 1 | pages = e1102805 | date = 2015 | pmid = 27066180 | pmc = 4802797 | doi = 10.1080/19420889.2015.1102805 }}

File:Drosophila circadian rhythm.jpg

Drosophila circadian rhythm is through a transcription-translation feedback loop. The core clock mechanism consists of two interdependent feedback loops, namely the PER/TIM loop and the CLK/CYC loop.{{cite journal | vauthors = Boothroyd CE, Young MW | title = The in(put)s and out(put)s of the Drosophila circadian clock | journal = Annals of the New York Academy of Sciences | volume = 1129 | issue = 1 | pages = 350–357 | date = 2008 | pmid = 18591494 | doi = 10.1196/annals.1417.006 | s2cid = 2639040 | bibcode = 2008NYASA1129..350B }} The CLK/CYC loop occurs during the day and initiates the transcription of the per and tim genes. But their proteins levels remain low until dusk, because during daylight also activates the doubletime (dbt) gene. DBT protein causes phosphorylation and turnover of monomeric PER proteins.{{cite journal | vauthors = Grima B, Lamouroux A, Chélot E, Papin C, Limbourg-Bouchon B, Rouyer F | title = The F-box protein slimb controls the levels of clock proteins period and timeless | journal = Nature | volume = 420 | issue = 6912 | pages = 178–182 | date = November 2002 | pmid = 12432393 | doi = 10.1038/nature01122 | s2cid = 4428779 | bibcode = 2002Natur.420..178G }}{{cite journal | vauthors = Ko HW, Jiang J, Edery I | title = Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime | journal = Nature | volume = 420 | issue = 6916 | pages = 673–678 | date = December 2002 | pmid = 12442174 | doi = 10.1038/nature01272 | s2cid = 4414176 | bibcode = 2002Natur.420..673K }} TIM is also phosphorylated by shaggy until sunset. After sunset, DBT disappears, so that PER molecules stably bind to TIM. PER/TIM dimer enters the nucleus several at night, and binds to CLK/CYC dimers. Bound PER completely stops the transcriptional activity of CLK and CYC.{{cite journal | vauthors = Helfrich-Förster C | title = Neurobiology of the fruit fly's circadian clock | journal = Genes, Brain and Behavior | volume = 4 | issue = 2 | pages = 65–76 | date = March 2005 | pmid = 15720403 | doi = 10.1111/j.1601-183X.2004.00092.x | s2cid = 26099539 | doi-access = free }}

In the early morning, light activates the cry gene and its protein CRY causes the breakdown of TIM. Thus PER/TIM dimer dissociates, and the unbound PER becomes unstable. PER undergoes progressive phosphorylation and ultimately degradation. Absence of PER and TIM allows activation of clk and cyc genes. Thus, the clock is reset to start the next circadian cycle.{{cite journal| vauthors = Lalchhandama K |title=The path to the 2017 Nobel Prize in Physiology or Medicine|journal=Science Vision|date=2017|volume=3|issue=Suppl|pages=1–13|url=https://www.researchgate.net/publication/321533113}}

This protein model was developed based on the oscillations of the PER and TIM proteins in the Drosophila.{{cite journal | vauthors = Leloup JC, Goldbeter A | title = A model for circadian rhythms in Drosophila incorporating the formation of a complex between the PER and TIM proteins | journal = Journal of Biological Rhythms | volume = 13 | issue = 1 | pages = 70–87 | date = February 1998 | pmid = 9486845 | doi = 10.1177/074873098128999934 | s2cid = 17944849 }} It is based on its predecessor, the PER model where it was explained how the PER gene and its protein influence the biological clock.{{cite journal | vauthors = Goldbeter A | title = A model for circadian oscillations in the Drosophila period protein (PER) | journal = Proceedings. Biological Sciences | volume = 261 | issue = 1362 | pages = 319–324 | date = September 1995 | pmid = 8587874 | doi = 10.1098/rspb.1995.0153 | s2cid = 7024361 | bibcode = 1995RSPSB.261..319G }} The model includes the formation of a nuclear PER-TIM complex which influences the transcription of the PER and the TIM genes (by providing negative feedback) and the multiple phosphorylation of these two proteins. The circadian oscillations of these two proteins seem to synchronise with the light-dark cycle even if they are not necessarily dependent on it.{{cite journal | vauthors = Goldbeter A | title = Computational approaches to cellular rhythms | journal = Nature | volume = 420 | issue = 6912 | pages = 238–245 | date = November 2002 | pmid = 12432409 | doi = 10.1038/nature01259 | s2cid = 452149 | bibcode = 2002Natur.420..238G }} Both PER and TIM proteins are phosphorylated and after they form the PER-TIM nuclear complex they return inside the nucleus to stop the expression of the PER and TIM mRNA. This inhibition lasts as long as the protein, or the mRNA is not degraded. When this happens, the complex releases the inhibition. Here can also be mentioned that the degradation of the TIM protein is sped up by light.

File:Circadian rhythm labeled.jpg illustrating the influence of light and darkness on circadian rhythms and related physiology and behavior through the suprachiasmatic nucleus in humans]]

The primary circadian clock in mammals is located in the suprachiasmatic nucleus (or nuclei) (SCN), a pair of distinct groups of cells located in the hypothalamus. Destruction of the SCN results in the complete absence of a regular sleep–wake rhythm. The SCN receives information about illumination through the eyes. The retina of the eye contains "classical" photoreceptors ("rods" and "cones"), which are used for conventional vision. But the retina also contains specialized ganglion cells that are directly photosensitive, and project directly to the SCN, where they help in the entrainment (synchronization) of this master circadian clock. The proteins involved in the SCN clock are homologous to those found in the fruit fly.{{cite web|title=Biological Clock in Mammals|url=http://www.hhmi.org/biointeractive/human-suprachiasmatic-nucleus|website=BioInteractive|date=4 February 2000|publisher=Howard Hughes Medical Institute|access-date=5 May 2015|archive-date=5 May 2015|archive-url=https://web.archive.org/web/20150505041251/http://www.hhmi.org/biointeractive/human-suprachiasmatic-nucleus|url-status=dead}}

These cells contain the photopigment melanopsin and their signals follow a pathway called the retinohypothalamic tract, leading to the SCN. If cells from the SCN are removed and cultured, they maintain their own rhythm in the absence of external cues.{{cite journal | vauthors = Welsh DK, Takahashi JS, Kay SA | title = Suprachiasmatic nucleus: cell autonomy and network properties | journal = Annual Review of Physiology | volume = 72 | pages = 551–77 | date = March 2010 | pmid = 20148688 | pmc = 3758475 | doi = 10.1146/annurev-physiol-021909-135919 }}

The SCN takes the information on the lengths of the day and night from the retina, interprets it, and passes it on to the pineal gland, a tiny structure shaped like a pine cone and located on the epithalamus. In response, the pineal secretes the hormone melatonin.{{cite journal | vauthors = Pfeffer M, Korf HW, Wicht H | title = Synchronizing effects of melatonin on diurnal and circadian rhythms | journal = General and Comparative Endocrinology | volume = 258 | pages = 215–221 | date = March 2018 | pmid = 28533170 | doi = 10.1016/j.ygcen.2017.05.013 }} Secretion of melatonin peaks at night and ebbs during the day and its presence provides information about night-length.

Several studies have indicated that pineal melatonin feeds back on SCN rhythmicity to modulate circadian patterns of activity and other processes. However, the nature and system-level significance of this feedback are unknown.{{cite news|vauthors=Kalpesh J|title=Wellness With Artificial Light|url=http://www.walalight.com/white-paper-released-on-promoting-elder-wellness-with-artificial-light/|access-date=11 January 2016|archive-date=4 March 2016|archive-url=https://web.archive.org/web/20160304110102/http://www.walalight.com/white-paper-released-on-promoting-elder-wellness-with-artificial-light/|url-status=dead}}

The circadian rhythms of humans can be entrained to slightly shorter and longer periods than the Earth's 24 hours. Researchers at Harvard have shown that human subjects can at least be entrained to a 23.5-hour cycle and a 24.65-hour cycle.{{MEDRS|date=November 2013}} {{cite journal | vauthors = Scheer FA, Wright KP, Kronauer RE, Czeisler CA | title = Plasticity of the intrinsic period of the human circadian timing system | journal = PLOS ONE | volume = 2 | issue = 8 | pages = e721 | date = August 2007 | pmid = 17684566 | pmc = 1934931 | doi = 10.1371/journal.pone.0000721 | bibcode = 2007PLoSO...2..721S | doi-access = free }}

File:Circadian rhythm.svg

{{see also|Sleep#Circadian clock|Phase response curve#Light}}

Early research into circadian rhythms suggested that most people preferred a day closer to 25 hours when isolated from external stimuli like daylight and timekeeping. However, this research was faulty because it failed to shield the participants from artificial light. Although subjects were shielded from time cues (like clocks) and daylight, the researchers were not aware of the phase-delaying effects of indoor electric lights.{{MEDRS|date=November 2013}} {{cite journal | vauthors = Duffy JF, Wright KP | s2cid = 20140030 | title = Entrainment of the human circadian system by light | journal = Journal of Biological Rhythms | volume = 20 | issue = 4 | pages = 326–38 | date = August 2005 | pmid = 16077152 | doi = 10.1177/0748730405277983 }}{{Dubious|reason=This is part review, part study, needs to be checked for proper use of secondary source|date=July 2014}} The subjects were allowed to turn on light when they were awake and to turn it off when they wanted to sleep. Electric light in the evening delayed their circadian phase.{{cite journal | vauthors = Khalsa SB, Jewett ME, Cajochen C, Czeisler CA | title = A phase response curve to single bright light pulses in human subjects | journal = The Journal of Physiology | volume = 549 | issue = Pt 3 | pages = 945–52 | date = June 2003 | pmid = 12717008 | pmc = 2342968 | doi = 10.1113/jphysiol.2003.040477 }} A more stringent study conducted in 1999 by Harvard University estimated the natural human rhythm to be closer to 24 hours and 11 minutes: much closer to the solar day.{{cite journal|url=http://news.harvard.edu/gazette/1999/07.15/bioclock24.html| vauthors = Cromie W |title=Human Biological Clock Set Back an Hour|journal=Harvard Gazette|date=1999-07-15|access-date=2015-07-04}} Consistent with this research was a more recent study from 2010, which also identified sex differences, with the circadian period for women being slightly shorter (24.09 hours) than for men (24.19 hours).{{cite journal | vauthors = Duffy JF, Cain SW, Chang AM, Phillips AJ, Münch MY, Gronfier C, Wyatt JK, Dijk DJ, Wright KP, Czeisler CA | title = Sex difference in the near-24-hour intrinsic period of the human circadian timing system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = Supplement_3 | pages = 15602–8 | date = September 2011 | pmid = 21536890 | pmc = 3176605 | doi = 10.1073/pnas.1010666108 | bibcode = 2011PNAS..10815602D | doi-access = free }} In this study, women tended to wake up earlier than men and exhibit a greater preference for morning activities than men, although the underlying biological mechanisms for these differences are unknown.

The classic phase markers for measuring the timing of a mammal's circadian rhythm are:

• melatonin secretion by the pineal gland,{{cite journal | vauthors = Benloucif S, Guico MJ, Reid KJ, Wolfe LF, L'hermite-Balériaux M, Zee PC | s2cid = 36360463 | title = Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans | journal = Journal of Biological Rhythms | volume = 20 | issue = 2 | pages = 178–88 | date = April 2005 | pmid = 15834114 | doi = 10.1177/0748730404273983 | doi-access = free }}
• core body temperature minimum, and
• plasma level of cortisol.{{cite journal | vauthors = Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE | title = Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis | journal = Psychoneuroendocrinology | volume = 83 | pages = 25–41 | date = September 2017 | pmid = 28578301 | pmc = 5568897 | doi = 10.1016/j.psyneuen.2017.05.018 }}

For temperature studies, subjects must remain awake but calm and semi-reclined in near darkness while their rectal temperatures are taken continuously. Though variation is great among normal chronotypes, the average human adult's temperature reaches its minimum at about 5:00 a.m., about two hours before habitual wake time. Baehr et al.{{cite journal | vauthors = Baehr EK, Revelle W, Eastman CI | s2cid = 6104127 | title = Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness | journal = Journal of Sleep Research | volume = 9 | issue = 2 | pages = 117–27 | date = June 2000 | pmid = 10849238 | doi = 10.1046/j.1365-2869.2000.00196.x | doi-access = free }} found that, in young adults, the daily body temperature minimum occurred at about 04:00 (4 a.m.) for morning types, but at about 06:00 (6 a.m.) for evening types. This minimum occurred at approximately the middle of the eight-hour sleep period for morning types, but closer to waking in evening types.

Melatonin is absent from the system or undetectably low during daytime. Its onset in dim light, dim-light melatonin onset (DLMO), at roughly 21:00 (9 p.m.) can be measured in the blood or the saliva. Its major metabolite can also be measured in morning urine. Both DLMO and the midpoint (in time) of the presence of the hormone in the blood or saliva have been used as circadian markers. However, newer research indicates that the melatonin offset may be the more reliable marker. Benloucif et al. found that melatonin phase markers were more stable and more highly correlated with the timing of sleep than the core temperature minimum. They found that both sleep offset and melatonin offset are more strongly correlated with phase markers than the onset of sleep. In addition, the declining phase of the melatonin levels is more reliable and stable than the termination of melatonin synthesis.

Other physiological changes that occur according to a circadian rhythm include heart rate and many cellular processes "including oxidative stress, cell metabolism, immune and inflammatory responses,Seizer L, Cornélissen-Guillaume G, Schiepek GK, Chamson E, Bliem HR and Schubert C (2022) About-Weekly Pattern in the Dynamic Complexity of a Healthy Subject's Cellular Immune Activity: A Biopsychosocial Analysis. Front. Psychiatry 13:799214. doi: 10.3389/fpsyt.2022.799214 epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment."{{cite web |url=http://www.nhlbi.nih.gov/research/reports/2014-circadian-clock-lung-health.htm |title=NHLBI Workshop: "Circadian Clock at the Interface of Lung Health and Disease" 28-29 April 2014 Executive Summary |author= |date=September 2014 |publisher=National Heart, Lung, and Blood Institute |access-date=20 September 2014 |archive-url=https://web.archive.org/web/20141004183349/http://www.nhlbi.nih.gov/research/reports/2014-circadian-clock-lung-health.htm |archive-date=2014-10-04 |url-status=dead }} In a study of young men, it was found that the heart rate reaches its lowest average rate during sleep, and its highest average rate shortly after waking.{{cite journal | vauthors = Degaute JP, van de Borne P, Linkowski P, Van Cauter E | title = Quantitative analysis of the 24-hour blood pressure and heart rate patterns in young men | journal = Hypertension | volume = 18 | issue = 2 | pages = 199–210 | date = August 1991 | pmid = 1885228 | doi = 10.1161/01.hyp.18.2.199 | doi-access = free }}

In contradiction to previous studies, it has been found that there is no effect of body temperature on performance on psychological tests. This is likely due to evolutionary pressures for higher cognitive function compared to the other areas of function examined in previous studies.{{cite journal| vauthors = Quartel L | title=The effect of the circadian rhythm of body temperature on A-level exam performance|journal=Undergraduate Journal of Psychology|date=2014|volume=27|issue=1|url=https://journals.uncc.edu/ujop/article/view/283/300}}

More-or-less independent circadian rhythms are found in many organs and cells in the body outside the suprachiasmatic nuclei (SCN), the "master clock". Indeed, neuroscientist Joseph Takahashi and colleagues stated in a 2013 article that "almost every cell in the body contains a circadian clock".{{cite journal | vauthors = Mohawk JA, Green CB, Takahashi JS | title = Central and peripheral circadian clocks in mammals | journal = Annual Review of Neuroscience | volume = 35 | pages = 445–62 | date = July 14, 2013 | pmid = 22483041 | pmc = 3710582 | doi = 10.1146/annurev-neuro-060909-153128 }} For example, these clocks, called peripheral oscillators, have been found in the adrenal gland, oesophagus, lungs, liver, pancreas, spleen, thymus, and skin.Id.{{cite journal | vauthors = Pendergast JS, Niswender KD, Yamazaki S | title = Tissue-specific function of Period3 in circadian rhythmicity | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e30254 | date = January 11, 2012 | pmid = 22253927 | pmc = 3256228 | doi = 10.1371/journal.pone.0030254 | bibcode = 2012PLoSO...730254P | doi-access = free }}{{cite news|title=Our Skin's Sense Of Time Helps Protect Against UV Damage| vauthors = Singh M |date=10 Oct 2013|website=NPR|access-date=19 Feb 2019|url=https://www.npr.org/sections/health-shots/2013/10/10/231437897/our-skins-sense-of-time-helps-protect-against-uv-damage}} There is also some evidence that the olfactory bulb{{cite journal | vauthors = Abraham U, Granada AE, Westermark PO, Heine M, Kramer A, Herzel H | title = Coupling governs entrainment range of circadian clocks | journal = Molecular Systems Biology | volume = 6 | pages = 438 | date = November 2010 | pmid = 21119632 | pmc = 3010105 | doi = 10.1038/msb.2010.92 }} and prostate{{cite journal | vauthors = Cao Q, Gery S, Dashti A, Yin D, Zhou Y, Gu J, Koeffler HP | title = A role for the clock gene per1 in prostate cancer | journal = Cancer Research | volume = 69 | issue = 19 | pages = 7619–25 | date = October 2009 | pmid = 19752089 | pmc = 2756309 | doi = 10.1158/0008-5472.CAN-08-4199 }} may experience oscillations, at least when cultured.

Though oscillators in the skin respond to light, a systemic influence has not been proven.{{cite journal | vauthors = Kawara S, Mydlarski R, Mamelak AJ, Freed I, Wang B, Watanabe H, Shivji G, Tavadia SK, Suzuki H, Bjarnason GA, Jordan RC, Sauder DN | title = Low-dose ultraviolet B rays alter the mRNA expression of the circadian clock genes in cultured human keratinocytes | journal = The Journal of Investigative Dermatology | volume = 119 | issue = 6 | pages = 1220–3 | date = December 2002 | pmid = 12485420 | doi = 10.1046/j.1523-1747.2002.19619.x | doi-access = free }} In addition, many oscillators, such as liver cells, for example, have been shown to respond to inputs other than light, such as feeding.{{cite journal | vauthors = Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U | title = Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus | journal = Genes & Development | volume = 14 | issue = 23 | pages = 2950–61 | date = December 2000 | pmid = 11114885 | pmc = 317100 | doi = 10.1101/gad.183500 }}

{{Further|Light effects on circadian rhythm}}

Light resets the biological clock in accordance with the phase response curve (PRC). Depending on the timing, light can advance or delay the circadian rhythm. Both the PRC and the required illuminance vary from species to species, and lower light levels are required to reset the clocks in nocturnal rodents than in humans.{{cite journal | vauthors = Duffy JF, Czeisler CA | title = Effect of Light on Human Circadian Physiology | journal = Sleep Medicine Clinics | volume = 4 | issue = 2 | pages = 165–177 | date = June 2009 | pmid = 20161220 | pmc = 2717723 | doi = 10.1016/j.jsmc.2009.01.004 }}

Various studies on humans have made use of enforced sleep/wake cycles strongly different from 24 hours, such as those conducted by Nathaniel Kleitman in 1938 (28 hours) and Derk-Jan Dijk and Charles Czeisler in the 1990s (20 hours). Because people with a normal (typical) circadian clock cannot entrain to such abnormal day/night rhythms,{{cite journal | vauthors = Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, Ronda JM, Silva EJ, Allan JS, Emens JS, Dijk DJ, Kronauer RE | title = Stability, precision, and near-24-hour period of the human circadian pacemaker | journal = Science | volume = 284 | issue = 5423 | pages = 2177–81 | date = June 1999 | pmid = 10381883 | doi = 10.1126/science.284.5423.2177 | s2cid = 8516106 }} this is referred to as a forced desynchrony protocol. Under such a protocol, sleep and wake episodes are uncoupled from the body's endogenous circadian period, which allows researchers to assess the effects of circadian phase (i.e., the relative timing of the circadian cycle) on aspects of sleep and wakefulness including sleep latency and other functions - both physiological, behavioral, and cognitive.{{Cite book | vauthors = Aldrich MS |title=Sleep medicine |url=https://books.google.com/books?id=1jScwMrsmAMC&q=experimenting+with+the+28+hour+day&pg=RA1-PA65 |year=1999 |isbn=978-0-19-512957-1 |publisher=Oxford University Press |location=New York}}{{cite journal | vauthors = Wyatt JK, Ritz-De Cecco A, Czeisler CA, Dijk DJ | s2cid = 4474347 | title = Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day | journal = The American Journal of Physiology | volume = 277 | issue = 4 Pt 2 | pages = R1152-63 | date = October 1999 | pmid = 10516257 | doi = 10.1152/ajpregu.1999.277.4.R1152 }}{{cite journal | vauthors = Wright KP, Hull JT, Czeisler CA | title = Relationship between alertness, performance, and body temperature in humans | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 283 | issue = 6 | pages = R1370-7 | date = December 2002 | pmid = 12388468 | doi = 10.1152/ajpregu.00205.2002 | citeseerx = 10.1.1.1030.9291 }}{{cite journal | vauthors = Zhou X, Ferguson SA, Matthews RW, Sargent C, Darwent D, Kennaway DJ, Roach GD | title = Sleep, wake and phase dependent changes in neurobehavioral function under forced desynchrony | journal = Sleep | volume = 34 | issue = 7 | pages = 931–41 | date = July 2011 | pmid = 21731143 | pmc = 3119835 | doi = 10.5665/SLEEP.1130 }}{{cite journal | vauthors = Kosmadopoulos A, Sargent C, Darwent D, Zhou X, Dawson D, Roach GD | s2cid = 11643058 | title = The effects of a split sleep-wake schedule on neurobehavioural performance and predictions of performance under conditions of forced desynchrony | journal = Chronobiology International | volume = 31 | issue = 10 | pages = 1209–17 | date = December 2014 | pmid = 25222348 | doi = 10.3109/07420528.2014.957763 }}

Studies also show that Cyclosa turbinata is unique in that its locomotor and web-building activity cause it to have an exceptionally short-period circadian clock, about 19 hours. When C. turbinata spiders are placed into chambers with periods of 19, 24, or 29 hours of evenly split light and dark, none of the spiders exhibited decreased longevity in their own circadian clock. These findings suggest that C. turbinata do not have the same costs of extreme desynchronization as do other species of animals.

File:Day Sleepers crop.jpg

The leading edge of circadian biology research is translation of basic body clock mechanisms into clinical tools, and this is especially relevant to the treatment of cardiovascular disease.{{cite journal | vauthors = Alibhai FJ, Tsimakouridze EV, Reitz CJ, Pyle WG, Martino TA | title = Consequences of Circadian and Sleep Disturbances for the Cardiovascular System | journal = The Canadian Journal of Cardiology | volume = 31 | issue = 7 | pages = 860–872 | date = July 2015 | pmid = 26031297 | doi = 10.1016/j.cjca.2015.01.015 }}{{cite journal | vauthors = Martino TA, Young ME | title = Influence of the cardiomyocyte circadian clock on cardiac physiology and pathophysiology | journal = Journal of Biological Rhythms | volume = 30 | issue = 3 | pages = 183–205 | date = June 2015 | pmid = 25800587 | doi = 10.1177/0748730415575246 | s2cid = 21868234 | doi-access = free }}{{cite journal | vauthors = Mistry P, Duong A, Kirshenbaum L, Martino TA | title = Cardiac Clocks and Preclinical Translation | journal = Heart Failure Clinics | volume = 13 | issue = 4 | pages = 657–672 | date = October 2017 | pmid = 28865775 | doi = 10.1016/j.hfc.2017.05.002 | doi-access = free }}{{cite journal | vauthors = Aziz IS, McMahon AM, Friedman D, Rabinovich-Nikitin I, Kirshenbaum LA, Martino TA | title = Circadian influence on inflammatory response during cardiovascular disease | journal = Current Opinion in Pharmacology | volume = 57 | pages = 60–70 | date = April 2021 | pmid = 33340915 | doi = 10.1016/j.coph.2020.11.007 | s2cid = 229332749 | doi-access = free }} Timing of medical treatment in coordination with the body clock, chronotherapeutics, may also benefit patients with hypertension (high blood pressure) by significantly increasing efficacy and reduce drug toxicity or adverse reactions.{{cite journal | vauthors = Grote L, Mayer J, Penzel T, Cassel W, Krzyzanek E, Peter JH, von Wichert P | title = Nocturnal hypertension and cardiovascular risk: consequences for diagnosis and treatment | journal = Journal of Cardiovascular Pharmacology | volume = 24 | pages = S26–S38 | year = 1994 | issue = Suppl 2 | doi = 10.1097/00005344-199412001-00006 | pmid = 7898092 }} 3) "Circadian Pharmacology" or drugs targeting the circadian clock mechanism have been shown experimentally in rodent models to significantly reduce the damage due to heart attacks and prevent heart failure.{{cite journal | vauthors = Reitz CJ, Alibhai FJ, Khatua TN, Rasouli M, Bridle BW, Burris TP, Martino TA | title = SR9009 administered for one day after myocardial ischemia-reperfusion prevents heart failure in mice by targeting the cardiac inflammasome | journal = Communications Biology | volume = 2 | pages = 353 | date = 2019 | pmid = 31602405 | pmc = 6776554 | doi = 10.1038/s42003-019-0595-z }} Importantly, for rational translation of the most promising Circadian Medicine therapies to clinical practice, it is imperative that we understand how it helps treat disease in both biological sexes.{{cite journal | vauthors = Alibhai FJ, Reitz CJ, Peppler WT, Basu P, Sheppard P, Choleris E, Bakovic M, Martino TA | title = Female ClockΔ19/Δ19 mice are protected from the development of age-dependent cardiomyopathy | journal = Cardiovascular Research | volume = 114 | issue = 2 | pages = 259–271 | date = February 2018 | pmid = 28927226 | doi = 10.1093/cvr/cvx185 | doi-access = free }}{{cite journal | vauthors = Alibhai FJ, LaMarre J, Reitz CJ, Tsimakouridze EV, Kroetsch JT, Bolz SS, Shulman A, Steinberg S, Burris TP, Oudit GY, Martino TA | title = Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease | journal = Journal of Molecular and Cellular Cardiology | volume = 105 | pages = 24–37 | date = April 2017 | pmid = 28223222 | doi = 10.1016/j.yjmcc.2017.01.008 | doi-access = free }}{{cite journal | vauthors = Bennardo M, Alibhai F, Tsimakouridze E, Chinnappareddy N, Podobed P, Reitz C, Pyle WG, Simpson J, Martino TA | title = Day-night dependence of gene expression and inflammatory responses in the remodeling murine heart post-myocardial infarction | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 311 | issue = 6 | pages = R1243–R1254 | date = December 2016 | pmid = 27733386 | doi = 10.1152/ajpregu.00200.2016 | s2cid = 36325095 }}{{Cite journal| vauthors = Pyle WG, Martino TA |date= October 2018 |title=Circadian rhythms influence cardiovascular disease differently in males and females: role of sex and gender |journal=Current Opinion in Physiology|language=en|volume=5|pages=30–37|doi=10.1016/j.cophys.2018.05.003|s2cid=80632426|issn=2468-8673|doi-access=free}}

Lighting requirements for circadian regulation are not simply the same as those for vision; planning of indoor lighting in offices and institutions is beginning to take this into account.{{cite journal | vauthors = Rea MS, Figueiro M, Bullough J |date=May 2002 |title=Circadian photobiology: an emerging framework for lighting practice and research |journal=Lighting Research & Technology |volume=34 |issue=3 |pages=177–187 |doi=10.1191/1365782802lt057oa |s2cid=109776194}} Animal studies on the effects of light in laboratory conditions have until recently considered light intensity (irradiance) but not color, which can be shown to "act as an essential regulator of biological timing in more natural settings".{{cite journal | vauthors = Walmsley L, Hanna L, Mouland J, Martial F, West A, Smedley AR, Bechtold DA, Webb AR, Lucas RJ, Brown TM | title = Colour as a signal for entraining the mammalian circadian clock | journal = PLOS Biology | volume = 13 | issue = 4 | pages = e1002127 | date = April 2015 | pmid = 25884537 | pmc = 4401556 | doi = 10.1371/journal.pbio.1002127 | doi-access = free }}

Blue LED lighting suppresses melatonin production five times more than the orange-yellow high-pressure sodium (HPS) light; a metal halide lamp, which is white light, suppresses melatonin at a rate more than three times greater than HPS.{{Cite journal | vauthors = Hardt R |date=1970-01-01 |title=The Dangers of LED-Blue light-The Suppression of Melatonin-Resulting in-Insomnia-And Cancers {{pipe}} Robert Hardt |url=https://www.academia.edu/5960717 |access-date=2016-12-24 |website=Academia.edu}}{{Dead link|date=December 2021|bot=InternetArchiveBot|fix-attempted=yes}} Depression symptoms from long term nighttime light exposure can be undone by returning to a normal cycle.{{cite journal | vauthors = Bedrosian TA, Nelson RJ | title = Timing of light exposure affects mood and brain circuits | journal = Translational Psychiatry | volume = 7 | issue = 1 | pages = e1017 | date = January 2017 | pmid = 28140399 | pmc = 5299389 | doi = 10.1038/tp.2016.262 }}

Due to the nature of work of airline pilots, who often cross several time zones and regions of sunlight and darkness in one day, and spend many hours awake both day and night, they are often unable to maintain sleep patterns that correspond to the natural human circadian rhythm; this situation can easily lead to fatigue. The NTSB cites this as contributing to many accidents,[http://www.aviationweek.com/aw/jsp_includes/articlePrint.jsp?storyID=news/FATIGex.xml&headLine=null]{{dead link|date=December 2016}} and has conducted several research studies in order to find methods of combating fatigue in pilots.Circadian Rhythm Disruption and Flying. FAA at https://www.faa.gov/pilots/safety/pilotsafetybrochures/media/Circadian_Rhythm.pdf {{Webarchive|url=https://web.archive.org/web/20170501112906/https://www.faa.gov/pilots/safety/pilotsafetybrochures/media/Circadian_Rhythm.pdf|date=2017-05-01}}

Studies conducted on both animals and humans show major bidirectional relationships between the circadian system and abusive drugs. It is indicated that these abusive drugs affect the central circadian pacemaker. Individuals with substance use disorder display disrupted rhythms. These disrupted rhythms can increase the risk for substance abuse and relapse. It is possible that genetic and/or environmental disturbances to the normal sleep and wake cycle can increase the susceptibility to addiction.{{cite journal |vauthors=Logan RW, Williams WP, McClung CA |date=June 2014 |title=Circadian rhythms and addiction: mechanistic insights and future directions |journal=Behavioral Neuroscience |volume=128 |issue=3 |pages=387–412 |doi=10.1037/a0036268 |pmc=4041815 |pmid=24731209}}

It is difficult to determine if a disturbance in the circadian rhythm is at fault for an increase in prevalence for substance abuse—or if other environmental factors such as stress are to blame.

Changes to the circadian rhythm and sleep occur once an individual begins abusing drugs and alcohol. Once an individual stops using drugs and alcohol, the circadian rhythm continues to be disrupted.

Alcohol consumption disrupts circadian rhythms, with acute intake causing dose-dependent alterations in melatonin and cortisol levels, as well as core body temperature, which normalize the following morning, while chronic alcohol use leads to more severe and persistent disruptions that are associated with alcohol use disorders (AUD) and withdrawal symptoms.{{cite journal |last1=Meyrel |first1=M |last2=Rolland |first2=B |last3=Geoffroy |first3=PA |title=Alterations in circadian rhythms following alcohol use: A systematic review. |journal=Progress in Neuro-psychopharmacology & Biological Psychiatry |date=20 April 2020 |volume=99 |pages=109831 |doi=10.1016/j.pnpbp.2019.109831 |pmid=31809833}}

The stabilization of sleep and the circadian rhythm might possibly help to reduce the vulnerability to addiction and reduce the chances of relapse.

Circadian rhythms and clock genes expressed in brain regions outside the suprachiasmatic nucleus may significantly influence the effects produced by drugs such as cocaine.{{Cite journal |last1=Falcón |first1=Edgardo |last2=McClung |first2=Colleen A. |date=2009-01-01 |title=A role for the circadian genes in drug addiction |journal=Neuropharmacology |series=Frontiers in Addiction Research: Celebrating the 35th Anniversary of the National Institute on Drug Abuse |volume=56 |issue=Suppl 1 |pages=91–96 |doi=10.1016/j.neuropharm.2008.06.054 |pmid=18644396 |issn=0028-3908|pmc=2635341 }} Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.{{cite journal |vauthors=Prosser RA, Glass JD |date=June 2015 |title=Assessing ethanol's actions in the suprachiasmatic circadian clock using in vivo and in vitro approaches |journal=Alcohol |volume=49 |issue=4 |pages=321–339 |doi=10.1016/j.alcohol.2014.07.016 |pmc=4402095 |pmid=25457753}}

{{Further|Circadian rhythm sleep disorder}}

Disruption to rhythms usually has a negative effect. Many travelers have experienced the condition known as jet lag, with its associated symptoms of fatigue, disorientation and insomnia.{{Cite web |title=The science of jet lag |url=https://www.timeshifter.com/jet-lag/the-science-of-jet-lag |access-date=2023-01-03 |website=Timeshifter |language=en}}

A number of other disorders, such as bipolar disorder, depression, and some sleep disorders such as delayed sleep phase disorder (DSPD), are associated with irregular or pathological functioning of circadian rhythms.{{cite journal | vauthors = Gold AK, Kinrys G | title = Treating Circadian Rhythm Disruption in Bipolar Disorder | journal = Current Psychiatry Reports | volume = 21 | issue = 3 | pages = 14 | date = March 2019 | pmid = 30826893 | pmc = 6812517 | doi = 10.1007/s11920-019-1001-8 }}{{cite journal | vauthors = Zhu L, Zee PC | title = Circadian rhythm sleep disorders | journal = Neurologic Clinics | volume = 30 | issue = 4 | pages = 1167–1191 | date = November 2012 | pmid = 23099133 | pmc = 3523094 | doi = 10.1016/j.ncl.2012.08.011 }}{{Cite journal |last1=Crouse |first1=Jacob J |last2=Carpenter |first2=Joanne S |last3=Song |first3=Yun Ju C |last4=Hockey |first4=Samuel J |last5=Naismith |first5=Sharon L |last6=Grunstein |first6=Ronald R |last7=Scott |first7=Elizabeth M |last8=Merikangas |first8=Kathleen R |last9=Scott |first9=Jan |last10=Hickie |first10=Ian B |date=September 2021 |title=Circadian rhythm sleep–wake disturbances and depression in young people: implications for prevention and early intervention |url=https://linkinghub.elsevier.com/retrieve/pii/S2215036621000341 |journal=The Lancet Psychiatry |language=en |volume=8 |issue=9 |pages=813–823 |doi=10.1016/S2215-0366(21)00034-1|pmid=34419186 }}{{Cite journal |last1=Scott |first1=Jan |last2=Etain |first2=Bruno |last3=Miklowitz |first3=David |last4=Crouse |first4=Jacob J. |last5=Carpenter |first5=Joanne |last6=Marwaha |first6=Steven |last7=Smith |first7=Daniel |last8=Merikangas |first8=Kathleen |last9=Hickie |first9=Ian |date=April 2022 |title=A systematic review and meta-analysis of sleep and circadian rhythms disturbances in individuals at high-risk of developing or with early onset of bipolar disorders |journal=Neuroscience & Biobehavioral Reviews |language=en |volume=135 |pages=104585 |doi=10.1016/j.neubiorev.2022.104585 |pmc=8957543 |pmid=35182537}}

Disruption to rhythms in the longer term is believed to have significant adverse health consequences for peripheral organs outside the brain, in particular in the development or exacerbation of cardiovascular disease.{{cite journal | vauthors = Zelinski EL, Deibel SH, McDonald RJ | title = The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body | journal = Neuroscience and Biobehavioral Reviews | volume = 40 | issue = 40 | pages = 80–101 | date = March 2014 | pmid = 24468109 | doi = 10.1016/j.neubiorev.2014.01.007 | s2cid = 6809964 }}Oritz-Tuldela E, Martinez-Nicolas A, Diaz-Mardomingo C, Garcia-Herranz S, Pereda-Perez I, Valencia A, Peraita H, Venero C, Madrid J, Rol M. 2014. The Characterization of Biological Rhythms in Mild Cognitive Impairment. BioMed Research International.

Studies have shown that maintaining normal sleep and circadian rhythms is important for many aspects of brain and health. A number of studies have also indicated that a power-nap, a short period of sleep during the day, can reduce stress and may improve productivity without any measurable effect on normal circadian rhythms.{{cite journal | vauthors = Hershner SD, Chervin RD | title = Causes and consequences of sleepiness among college students | journal = Nature and Science of Sleep | volume = 6 | pages = 73–84 | date = 2014-06-23 | pmid = 25018659 | pmc = 4075951 | doi = 10.2147/NSS.S62907 | doi-access = free }}{{cite journal | vauthors = Milner CE, Cote KA | title = Benefits of napping in healthy adults: impact of nap length, time of day, age, and experience with napping | journal = Journal of Sleep Research | volume = 18 | issue = 2 | pages = 272–281 | date = June 2009 | pmid = 19645971 | doi = 10.1111/j.1365-2869.2008.00718.x | s2cid = 22815227 | doi-access = free }}{{cite book | vauthors = Lovato N, Lack L |title=The effects of napping on cognitive functioning |year=2010 |isbn=978-0-444-53702-7 |series=Progress in Brain Research |volume=185 |pages=155–166 |doi=10.1016/B978-0-444-53702-7.00009-9 |pmid=21075238 }} Circadian rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness. A reversal{{Clarify|date=April 2019}} in the sleep–wake cycle may be a sign or complication of uremia,{{cite web |date=10 May 2006 |title=Renal Failure, Acute |url=http://www.emedicine.com/emerg/topic500.htm |access-date=2008-08-03 |publisher=eMedicine from WebMD |vauthors=Sinert T, Peacock PR}} azotemia or acute kidney injury.{{cite journal | vauthors = Maung SC, El Sara A, Chapman C, Cohen D, Cukor D | title = Sleep disorders and chronic kidney disease | journal = World Journal of Nephrology | volume = 5 | issue = 3 | pages = 224–232 | date = May 2016 | pmid = 27152260 | pmc = 4848147 | doi = 10.5527/wjn.v5.i3.224 | doi-access = free }}{{cite journal | vauthors = Nakano S, Uchida K, Kigoshi T, Azukizawa S, Iwasaki R, Kaneko M, Morimoto S | title = Circadian rhythm of blood pressure in normotensive NIDDM subjects. Its relationship to microvascular complications | journal = Diabetes Care | volume = 14 | issue = 8 | pages = 707–711 | date = August 1991 | pmid = 1954805 | doi = 10.2337/diacare.14.8.707 | s2cid = 12489921 }} Studies have also helped elucidate how light has a direct effect on human health through its influence on the circadian biology.{{cite journal | vauthors = Figueiro MG, Rea MS, Bullough JD | title = Does architectural lighting contribute to breast cancer? | journal = Journal of Carcinogenesis | volume = 5 | pages = 20 | date = August 2006 | pmid = 16901343 | pmc = 1557490 | doi = 10.1186/1477-3163-5-20 | doi-access = free }}

One of the first studies to determine how disruption of circadian rhythms causes cardiovascular disease was performed in the Tau hamsters, which have a genetic defect in their circadian clock mechanism.{{cite journal | vauthors = Martino TA, Oudit GY, Herzenberg AM, Tata N, Koletar MM, Kabir GM, Belsham DD, Backx PH, Ralph MR, Sole MJ | title = Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 294 | issue = 5 | pages = R1675–R1683 | date = May 2008 | pmid = 18272659 | doi = 10.1152/ajpregu.00829.2007 | s2cid = 13356393 }} When maintained in a 24-hour light-dark cycle that was "out of sync" with their normal 22 circadian mechanism they developed profound cardiovascular and renal disease; however, when the Tau animals were raised for their entire lifespan on a 22-hour daily light-dark cycle they had a healthy cardiovascular system. The adverse effects of circadian misalignment on human physiology has been studied in the laboratory using a misalignment protocol,{{cite journal | vauthors = Scheer FA, Hilton MF, Mantzoros CS, Shea SA | title = Adverse metabolic and cardiovascular consequences of circadian misalignment | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 11 | pages = 4453–4458 | date = March 2009 | pmid = 19255424 | pmc = 2657421 | doi = 10.1073/pnas.0808180106 | doi-access = free | bibcode = 2009PNAS..106.4453S }}{{cite journal | vauthors = Scheer FA, Michelson AD, Frelinger AL, Evoniuk H, Kelly EE, McCarthy M, Doamekpor LA, Barnard MR, Shea SA | title = The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors | journal = PLOS ONE | volume = 6 | issue = 9 | pages = e24549 | date = 2011 | pmid = 21931750 | pmc = 3169622 | doi = 10.1371/journal.pone.0024549 | doi-access = free | bibcode = 2011PLoSO...624549S }} and by studying shift workers.{{cite journal | vauthors = Rabinovich-Nikitin I, Lieberman B, Martino TA, Kirshenbaum LA | title = Circadian-Regulated Cell Death in Cardiovascular Diseases | journal = Circulation | volume = 139 | issue = 7 | pages = 965–980 | date = February 2019 | pmid = 30742538 | doi = 10.1161/CIRCULATIONAHA.118.036550 | s2cid = 73436800 | doi-access = free }} Circadian misalignment is associated with many risk factors of cardiovascular disease. High levels of the atherosclerosis biomarker, resistin, have been reported in shift workers indicating the link between circadian misalignment and plaque build up in arteries.{{cite journal | vauthors = Kervezee L, Kosmadopoulos A, Boivin DB | title = Metabolic and cardiovascular consequences of shift work: The role of circadian disruption and sleep disturbances | journal = The European Journal of Neuroscience | volume = 51 | issue = 1 | pages = 396–412 | date = January 2020 | pmid = 30357975 | doi = 10.1111/ejn.14216 | s2cid = 53031343 | url = https://escholarship.mcgill.ca/concern/articles/gt54kt25z }} Additionally, elevated triacylglyceride levels (molecules used to store excess fatty acids) were observed and contribute to the hardening of arteries, which is associated with cardiovascular diseases including heart attack, stroke and heart disease.{{cite journal | vauthors = Proper KI, van de Langenberg D, Rodenburg W, Vermeulen RC, van der Beek AJ, van Steeg H, van Kerkhof LW | title = The Relationship Between Shift Work and Metabolic Risk Factors: A Systematic Review of Longitudinal Studies | language = English | journal = American Journal of Preventive Medicine | volume = 50 | issue = 5 | pages = e147–e157 | date = May 2016 | pmid = 26810355 | doi = 10.1016/j.amepre.2015.11.013 | hdl = 1874/346787 | hdl-access = free }} Shift work and the resulting circadian misalignment is also associated with hypertension.

Obesity and diabetes are associated with lifestyle and genetic factors. Among those factors, disruption of the circadian clockwork and/or misalignment of the circadian timing system with the external environment (e.g., light–dark cycle) can play a role in the development of metabolic disorders.

Shift work or chronic jet lag have profound consequences for circadian and metabolic events in the body. Animals that are forced to eat during their resting period show increased body mass and altered expression of clock and metabolic genes.{{cite journal | vauthors = Johnston JD | title = Physiological responses to food intake throughout the day | journal = Nutrition Research Reviews | volume = 27 | issue = 1 | pages = 107–18 | date = June 2014 | pmid = 24666537 | pmc = 4078443 | doi = 10.1017/S0954422414000055 }} In humans, shift work that favours irregular eating times is associated with altered insulin sensitivity, diabetes and higher body mass.{{cite journal | vauthors = Delezie J, Challet E | title = Interactions between metabolism and circadian clocks: reciprocal disturbances | journal = Annals of the New York Academy of Sciences | volume = 1243 | issue = 1 | pages = 30–46 | date = December 2011 | pmid = 22211891 | doi = 10.1111/j.1749-6632.2011.06246.x | url = https://univoak.eu/islandora/object/islandora%3A64197/datastream/PDF/view | bibcode = 2011NYASA1243...30D | s2cid = 43621902 }} {{cite journal | vauthors = van Drongelen A, Boot CR, Merkus SL, Smid T, van der Beek AJ | title = The effects of shift work on body weight change - a systematic review of longitudinal studies | journal = Scandinavian Journal of Work, Environment & Health | volume = 37 | issue = 4 | pages = 263–275 | date = July 2011 | pmid = 21243319 | doi = 10.5271/sjweh.3143 | s2cid = 35457083 | doi-access = free }}

Reduced cognitive function has been associated with circadian misalignment. Chronic shift workers display increased rates of operational error, impaired visual-motor performance and processing efficacy which can lead to both a reduction in performance and potential safety issues.{{cite journal | vauthors = Chellappa SL, Morris CJ, Scheer FA | title = Effects of circadian misalignment on cognition in chronic shift workers | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 699 | date = January 2019 | pmid = 30679522 | pmc = 6346005 | doi = 10.1038/s41598-018-36762-w | bibcode = 2019NatSR...9..699C }} Increased risk of dementia is associated with chronic night shift workers compared to day shift workers, particularly for individuals over 50 years old.{{cite journal | vauthors = Leng Y, Musiek ES, Hu K, Cappuccio FP, Yaffe K | title = Association between circadian rhythms and neurodegenerative diseases | journal = The Lancet. Neurology | volume = 18 | issue = 3 | pages = 307–318 | date = March 2019 | pmid = 30784558 | pmc = 6426656 | doi = 10.1016/S1474-4422(18)30461-7 }}{{cite journal | vauthors = Wang ZZ, Sun Z, Zhang ML, Xiong K, Zhou F | title = Relationship between shift work, night work, and subsequent dementia: A systematic evaluation and meta-analysis | journal = Frontiers in Neurology | volume = 13 | pages = 997181 | date = 2022-11-07 | pmid = 36419534 | pmc = 9677942 | doi = 10.3389/fneur.2022.997181 | doi-access = free }}{{cite journal | vauthors = Leso V, Caturano A, Vetrani I, Iavicoli I | title = Shift or night shift work and dementia risk: a systematic review | journal = European Review for Medical and Pharmacological Sciences | volume = 25 | issue = 1 | pages = 222–232 | date = January 2021 | pmid = 33506911 | doi = 10.26355/eurrev_202101_24388 }}

In 2017, Jeffrey C. Hall, Michael W. Young, and Michael Rosbash were awarded Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".{{cite news | vauthors = Cha AE |date=October 2, 2017 |title=Nobel in physiology, medicine awarded to three Americans for discovery of 'clock genes' |url=https://www.washingtonpost.com/news/to-your-health/wp/2017/10/02/nobel-prize-in-medicine-or-physiology-awarded-to-tktk/ |newspaper=The Washington Post |access-date=October 2, 2017 }}{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/2017/press.html |title=The 2017 Nobel Prize in Physiology or Medicine – Press Release|publisher=The Nobel Foundation |date=October 2, 2017 |access-date=October 2, 2017}}

Circadian rhythms was taken as an example of scientific knowledge being transferred into the public sphere.{{cite journal | vauthors = Benjakob O, Aviram R | title = A Clockwork Wikipedia: From a Broad Perspective to a Case Study | journal = Journal of Biological Rhythms | volume = 33 | issue = 3 | pages = 233–244 | date = June 2018 | pmid = 29665713 | doi = 10.1177/0748730418768120 | s2cid = 4933390 | doi-access = free }}

{{colbegin}}

• Actigraphy (also known as actimetry)
• ARNTL
• ARNTL2
• Bacterial circadian rhythms
• Circadian rhythm sleep disorders, such as
• Advanced sleep phase disorder
• Delayed sleep phase disorder
• Non-24-hour sleep–wake disorder
• Chronobiology
• Chronodisruption
• CLOCK
• Circasemidian rhythm
• Circaseptan, 7-day biological cycle
• Cryptochrome
• CRY1 and CRY2: the cryptochrome family genes
• Diurnal cycle
• Light effects on circadian rhythm
• Light in school buildings
• PER1, PER2, and PER3: the period family genes
• Photosensitive ganglion cell: part of the eye which is involved in regulating circadian rhythm.
• Polyphasic sleep
• Rev-ErbA alpha
• Segmented sleep
• Sleep architecture (sleep in humans)
• Sleep in non-human animals
• Stefania Follini
• Ultradian rhythm

{{colend}}

{{Reflist|32em}}

{{Refbegin|32em}}

• {{cite book | veditors = Aschoff J | date = 1965 | title = Circadian Clocks | publisher = North Holland Press | location = Amsterdam }}
• {{cite journal | vauthors = Avivi A, Albrecht U, Oster H, Joel A, Beiles A, Nevo E | title = Biological clock in total darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 24 | pages = 13751–6 | date = November 2001 | pmid = 11707566 | pmc = 61113 | doi = 10.1073/pnas.181484498 | bibcode = 2001PNAS...9813751A | doi-access = free }}
• {{cite journal | vauthors = Avivi A, Oster H, Joel A, Beiles A, Albrecht U, Nevo E | title = Circadian genes in a blind subterranean mammal II: conservation and uniqueness of the three Period homologs in the blind subterranean mole rat, Spalax ehrenbergi superspecies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 18 | pages = 11718–23 | date = September 2002 | pmid = 12193657 | pmc = 129335 | doi = 10.1073/pnas.182423299 | bibcode = 2002PNAS...9911718A | doi-access = free }}
• {{cite journal | vauthors = Li D, Ma S, Guo D, Cheng T, Li H, Tian Y, Li J, Guan F, Yang B, Wang J | title = Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury | journal = Cellular and Molecular Neurobiology | volume = 36 | issue = 7 | pages = 1045–55 | date = October 2016 | pmid = 26886755 | pmc = 4967018 | doi = 10.1007/s10571-015-0295-2 }}
• {{cite journal | vauthors = Ditty JL, Williams SB, Golden SS | s2cid = 36703896 | title = A cyanobacterial circadian timing mechanism | journal = Annual Review of Genetics | volume = 37 | pages = 513–43 | year = 2003 | pmid = 14616072 | doi = 10.1146/annurev.genet.37.110801.142716 }}
• {{cite book | vauthors = Dunlap JC, Loros J, DeCoursey PJ | date = 2003 | title = Chronobiology: Biological Timekeeping | url = https://archive.org/details/chronobiologybio0000unse | url-access = registration | publisher = Sinauer | location = Sunderland | isbn = 978-0-87893-149-1 }}
• {{cite journal | vauthors = Dvornyk V, Vinogradova O, Nevo E | title = Origin and evolution of circadian clock genes in prokaryotes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2495–500 | date = March 2003 | pmid = 12604787 | pmc = 151369 | doi = 10.1073/pnas.0130099100 | bibcode = 2003PNAS..100.2495D | doi-access = free }}
• {{cite book | vauthors = Koukkari WL, Sothern RB | date = 2006 | title = Introducing Biological Rhythms | publisher = Springer | location = New York }}
• {{cite journal | vauthors = Martino T, Arab S, Straume M, Belsham DD, Tata N, Cai F, Liu P, Trivieri M, Ralph M, Sole MJ | s2cid = 871822 | title = Day/night rhythms in gene expression of the normal murine heart | journal = Journal of Molecular Medicine | volume = 82 | issue = 4 | pages = 256–64 | date = April 2004 | pmid = 14985853 | doi = 10.1007/s00109-003-0520-1 }}
• {{cite book | vauthors = Refinetti R | date = 2006 | title = Circadian Physiology | edition = 2nd | publisher = CRC Press | location = Boca Raton }}
• {{cite journal | vauthors = Takahashi JS, Zatz M | title = Regulation of circadian rhythmicity | journal = Science | volume = 217 | issue = 4565 | pages = 1104–11 | date = September 1982 | pmid = 6287576 | doi = 10.1126/science.6287576 | bibcode = 1982Sci...217.1104T }}
• {{cite journal | vauthors = Tomita J, Nakajima M, Kondo T, Iwasaki H | s2cid = 9447128 | title = No transcription-translation feedback in circadian rhythm of KaiC phosphorylation | journal = Science | volume = 307 | issue = 5707 | pages = 251–4 | date = January 2005 | pmid = 15550625 | doi = 10.1126/science.1102540 | bibcode = 2005Sci...307..251T | doi-access = free }}
• {{Cite book | vauthors = Moore-Ede MC, Sulzman FM, Fuller CA |year=1982 |title=The Clocks that Time Us: Physiology of the Circadian Timing System |publisher=Harvard University Press |location=Cambridge, Massachusetts |isbn=978-0-674-13581-9 |url-access=registration |url=https://archive.org/details/clocksthattimeus0000moor }}

{{Refend}}

{{Commons category}}

{{Light Ethology}}

{{Authority control}}

{{DEFAULTSORT:Circadian Rhythm}}

Category:Sleep

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