A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours.
It can refer to any process that originates within an organism (i.e.,
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
) and responds to the environment (
entrained by the environment). These 24-hour rhythms are driven by a
circadian clock
A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...
, and they have been widely observed in
animals
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...
,
plants
Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all curr ...
,
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
and
cyanobacteria
Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
.
The term ''circadian'' comes from the
Latin
Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
''
circa
Circa is a word of Latin origin meaning 'approximately'.
Circa or CIRCA may also refer to:
* CIRCA (art platform), art platform based in London
* Circa (band), a progressive rock supergroup
* Circa (company), an American skateboard footwear com ...
'', meaning "approximately", and ''dies'', meaning "day". Processes with 24-hour cycles are more generally called diurnal rhythms; diurnal rhythms should not be called circadian rhythms unless they can be confirmed as endogenous, and not environmental.
Although circadian rhythms are endogenous, they are adjusted to the local environment by external cues called
zeitgeber
A zeitgeber () is any external or environmental cue that entrains or synchronizes an organism's biological rhythms, usually naturally occurring and serving to entrain to the Earth's 24-hour light/dark and 12-month cycles.
History
The term ' (; ) ...
s (German for "time givers"), which include light, temperature and
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
cycles. In clinical settings, an abnormal circadian rhythm in humans is known as a
circadian rhythm sleep disorder
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be ...
.
History
While there are multiple mentions of "natural body cycle" in Eastern and Native American cultures, the earliest recorded Western account of a circadian process is credited to
Theophrastus
Theophrastus (; grc-gre, Θεόφραστος ; c. 371c. 287 BC), a Greek philosopher and the successor to Aristotle in the Peripatetic school. He was a native of Eresos in Lesbos.Gavin Hardy and Laurence Totelin, ''Ancient Botany'', Routledge ...
, dating from the 4th century BC, probably provided to him by report of
Androsthenes, a
ship's captain
A sea captain, ship's captain, captain, master, or shipmaster, is a high-grade licensed mariner who holds ultimate command and responsibility of a merchant vessel.Aragon and Messner, 2001, p.3. The captain is responsible for the safe and efficie ...
serving under
Alexander the Great
Alexander III of Macedon ( grc, wikt:Ἀλέξανδρος, Ἀλέξανδρος, Alexandros; 20/21 July 356 BC – 10/11 June 323 BC), commonly known as Alexander the Great, was a king of the Ancient Greece, ancient Greek kingdom of Maced ...
. In his book, 'Περὶ φυτῶν ἱστορία', or 'Enquiry into plants', Theophrastus describes a "tree with many leaves like the
rose
A rose is either a woody perennial flowering plant of the genus ''Rosa'' (), in the family Rosaceae (), or the flower it bears. There are over three hundred species and tens of thousands of cultivars. They form a group of plants that can be ...
, 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." The tree mentioned by him was much later identified as the
tamarind
Tamarind (''Tamarindus indica'') is a Legume, leguminous tree bearing edible fruit that is probably indigenous to tropical Africa. The genus ''Tamarindus'' is monotypic taxon, monotypic, meaning that it contains only this species. It belongs ...
tree by the botanist, H Bretzl, in his book on the botanical findings of the Alexandrian campaigns.
The observation of a circadian or diurnal process in humans is mentioned in
Chinese medical texts
Chinese can refer to:
* Something related to China
* Chinese people, people of Chinese nationality, citizenship, and/or ethnicity
**''Zhonghua minzu'', the supra-ethnic concept of the Chinese nation
** List of ethnic groups in China, people of v ...
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''.
In 1729, French scientist
Jean-Jacques d'Ortous de Mairan
Jean-Jacques d'Ortous de Mairan (26 November 1678 – 20 February 1771) was a French geophysicist, astronomer and most notably, chronobiologist, was born in the town of Béziers on 26 November 1678. De Mairan lost his father, François d'Ortou ...
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
''Mimosa pudica'' (from la, pudica "shy, bashful or shrinking"; also called sensitive plant, sleepy plant, action plant, touch-me-not, shameplant) is a creeping annual or perennial flowering plant of the pea/legume family Fabaceae. It is often g ...
'' persisted, even when the plants were kept in constant darkness.
In 1896, Patrick and Gilbert observed that during a prolonged period of
sleep deprivation
Sleep deprivation, also known as sleep insufficiency or sleeplessness, is the condition of not having adequate duration and/or quality of sleep to support decent alertness, performance, and health. It can be either chronic or acute and may vary ...
, sleepiness increases and decreases with a period of approximately 24 hours. In 1918,
J.S. Szymanski
JS or js may refer to:
Computing
* JavaScript, a high-level, just-in-time compiled, object-oriented programming language
* JScript, Microsoft's dialect of the ECMAScript standard used in Internet Explorer
Businesses and organizations
* Jonge Soc ...
showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature.
In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees.
Auguste Forel
Auguste-Henri Forel (1 September 1848 – 27 July 1931) was a Swiss myrmecologist, neuroanatomist, psychiatrist and eugenicist, notable for his investigations into the structure of the human brain and that of ants. For example, he is considered a ...
,
Ingeborg Beling
Ingeborg Beling (1904-1988) was a German Ethology, ethologist from the early 20th century who worked in the field of chronobiology. She studied at the University of Munich under the direction of Karl Von Frisch and is known for her research on the ...
, and Oskar Wahl conducted numerous experiments to determine whether this rhythm was attributable to an endogenous clock. The existence of circadian rhythm was independently discovered in
fruit flies
Fruit fly may refer to:
Organisms
* Drosophilidae, a family of small flies, including:
** ''Drosophila'', the genus of small fruit flies and vinegar flies
** ''Drosophila melanogaster'' or common fruit fly
** ''Drosophila suzukii'' or Asian fruit ...
in 1935 by two German zoologists,
Hans Kalmus
Hans may refer to:
__NOTOC__ People
* Hans (name), a masculine given name
* Hans Raj Hans, Indian singer and politician
** Navraj Hans, Indian singer, actor, entrepreneur, cricket player and performer, son of Hans Raj Hans
** Yuvraj Hans, Punjabi ...
and
Erwin Bünning.
In 1954, an important experiment reported by
Colin Pittendrigh
Colin Stephenson Pittendrigh (October 13, 1918 – March 19, 1996)
"Colin Pittendrigh, 'Father of biological clock,' ...
demonstrated that
eclosion
A pupa ( la, pupa, "doll"; plural: ''pupae'') is the life stage of some insects undergoing transformation between immature and mature stages. Insects that go through a pupal stage are holometabolous: they go through four distinct stages in their ...
(the process of
pupa
A pupa ( la, pupa, "doll"; plural: ''pupae'') is the life stage of some insects undergoing transformation between immature and mature stages. Insects that go through a pupal stage are holometabolous: they go through four distinct stages in their ...
turning into adult) in ''
Drosophila pseudoobscura
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' 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.
[
The term ''circadian'' was coined by Franz Halberg in 1959. According to Halberg's original definition:
In 1977, the International Committee on Nomenclature of the ]International Society for Chronobiology
International is an adjective (also used as a noun) meaning "between nations".
International may also refer to:
Music Albums
* International (Kevin Michael album), ''International'' (Kevin Michael album), 2011
* International (New Order album), ' ...
formally adopted the definition:
Ron Konopka
Ronald J. Konopka (1947-2015) was an American geneticist who studied chronobiology. He made his most notable contribution to the field while working with ''Drosophila'' in the lab of Seymour Benzer at the California Institute of Technology. Durin ...
and Seymour Benzer
Seymour Benzer (October 15, 1921 – November 30, 2007) was an American physicist, molecular biologist and behavioral geneticist. His career began during the molecular biology revolution of the 1950s, and he eventually rose to prominence in the ...
identified the first clock mutation in ''Drosophila'' in 1971, naming the gene "period
Period may refer to:
Common uses
* Era, a length or span of time
* Full stop (or period), a punctuation mark
Arts, entertainment, and media
* Period (music), a concept in musical composition
* Periodic sentence (or rhetorical period), a concept ...
" (''per'') gene, the first discovered genetic determinant of behavioral rhythmicity. ''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. 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. 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.
Joseph Takahashi
Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group di ...
discovered the first mammalian circadian clock mutation (''clockΔ19'') using mice in 1994. 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.
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
Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morn ...
is caused by a single amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
change, S662➔G, in the human PER2 protein.
Criteria
To be called circadian, a biological rhythm must meet these three general criteria:
# The rhythm has an endogenous free-running period 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
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
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.
# The rhythms are entrainable. The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment
Entrainment may refer to:
* Air entrainment, the intentional creation of tiny air bubbles in concrete
* Brainwave entrainment, the practice of entraining one's brainwaves to a desired frequency
* Entrainment (biomusicology), the synchronization o ...
. The external stimulus used to entrain a rhythm is called the Zeitgeber
A zeitgeber () is any external or environmental cue that entrains or synchronizes an organism's biological rhythms, usually naturally occurring and serving to entrain to the Earth's 24-hour light/dark and 12-month cycles.
History
The term ' (; ) ...
, or "time giver". Travel across time zone
A time zone is an area which observes a uniform standard time for legal, Commerce, commercial and social purposes. Time zones tend to follow the boundaries between Country, countries and their Administrative division, subdivisions instead of ...
s illustrates the ability of the human biological clock to adjust to the local time; a person will usually experience jet lag
Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. fr ...
before entrainment of their circadian clock has brought it into sync with local time.
# 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
Kinetics ( grc, κίνησις, , kinesis, ''movement'' or ''to move'') may refer to:
Science and medicine
* Kinetics (physics), the study of motion and its causes
** Rigid body kinetics, the study of the motion of rigid bodies
* Chemical ki ...
of all molecular processes in their . 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.
Origin
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''. This is suggested by the maintenance (heritability) of circadian rhythms in fruit flies after several hundred generations in constant laboratory conditions, 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
Quail is a collective name for several genera of mid-sized birds generally placed in the order Galliformes. The collective noun for a group of quail is a flock, covey, or bevy.
Old World quail are placed in the family Phasianidae, and New Wor ...
.
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
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
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. Recent studies instead highlight the importance of co-evolution of redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
proteins with circadian oscillators in all three domains of life following the Great Oxidation Event
The Great Oxidation Event (GOE), also called the Great Oxygenation Event, the Oxygen Catastrophe, the Oxygen Revolution, the Oxygen Crisis, or the Oxygen Holocaust, was a time interval during the Paleoproterozoic era when the Earth's atmosphere ...
approximately 2.3 billion years ago. The current view is that circadian changes in environmental oxygen levels and the production of reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(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 clock
A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...
s are bacterial circadian rhythms Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three characteristics: (a) in constant conditions (i.e. constant temperature and either constant light or constant darkness ) the ...
, exemplified by the prokaryote cyanobacteria
Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
. Recent research has demonstrated that the circadian clock of ''Synechococcus elongatus
''Synechococcus elongatus'' is a unicellular cyanobacterium that has a rapid autotrophic growth comparable to yeast. Its ability to grow rapidly using sunlight has implications for biotechnological applications, especially when incorporating gene ...
'' can be reconstituted ''in vitro'' with just the three proteins (KaiA Kaia or KAIA may refer to:
* Kaia (name), including a list of people with the name
* KaiA, a gene
* KAIA (group), a Filipino girl group
* KAIA (FM), radio station (91.5 FM) licensed to Blytheville, Arkansas, United States
* King Abdulaziz Intern ...
, KaiB Kaib, KaiB, or KAIB may refer to:
* KAIB (FM), one of the radio stations of Air 1
* KaiB, a gene
* KAI Bandara, an Indonesian railway operator
* Korea Aviation Accident Investigation Board
The Korea Aviation Accident Investigation Board (KAIB, ...
, KaiC
KaiC is a gene belonging to the KaiABC gene cluster (with KaiA, and KaiB) that, together, regulate bacterial circadian rhythms, specifically in cyanobacteria. KaiC encodes for the KaiC protein, which interacts with the KaiA and KaiB proteins in ...
) 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
A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
circadian timekeeper were dependent upon a DNA transcription/translation feedback mechanism.
A defect in the human homologue of the ''Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' "period
Period may refer to:
Common uses
* Era, a length or span of time
* Full stop (or period), a punctuation mark
Arts, entertainment, and media
* Period (music), a concept in musical composition
* Periodic sentence (or rhetorical period), a concept ...
" gene was identified as a cause of the sleep disorder FASPS (Familial advanced sleep phase syndrome
Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morn ...
), 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.
It is now known that the molecular circadian clock can function within a single cell. That is, it is cell-autonomous. This was shown by Gene Block
Gene David Block (born August 17, 1948) is an American biologist who has served as the current and 6th chancellor of the University of California, Los Angeles since August 2007.
Block has served as provost and professor of biology at the Univer ...
in isolated mollusk basal retinal neurons (BRNs). At the same time, different cells may communicate with each other resulting in a synchronised output of electrical signaling. These may interface with endocrine gland
Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid ...
s of the brain to result in periodic release of hormones. The receptors for these hormones may be located far across the body and synchronise 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 synchronised. This is how the timing of, for example, sleep/wake, body temperature, thirst, and appetite are coordinately controlled by the biological clock.
Importance in animals
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
''Brain Wave'' is a science fiction novel by American writer Poul Anderson, first published in serial form in ''Space Science Fiction'' in 1953, and then as a novel in 1954. Anderson had said that he could consider it one of his top five books. Th ...
activity, hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
production, cell regeneration, and other biological activities. In addition, photoperiodism
Photoperiodism is the physiological reaction of organisms to the length of night or a dark period. It occurs in plants and animals. Plant photoperiodism can also be defined as the developmental responses of plants to the relative lengths of light a ...
, 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.
Effect of circadian disruption
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.[ ] In mice, deletion of the Rev-ErbA alpha
Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the '' ...
clock gene can result in diet-induced obesity and changes the balance between glucose and lipid utilization, predisposing to diabetes. 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.[ ][ ]
Effect of light–dark cycle
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
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
period, is shorter or longer than 24 hours. The environmental cues that reset the rhythms each day are called zeitgebers (from the German, "time-givers").[ ] Totally blind subterranean mammals (e.g., blind mole rat
The blind mole-rats, also known as the fossorial or subterranean mole rats, are a subfamily (Spalacinae) of rodents in the family Spalacidae, found in eastern Europe and western & central Asia. The hystricognath mole-rats of the family Bathyergi ...
''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.
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
In chronobiology, an ultradian rhythm is a recurrent period or cycle repeated throughout a 24-hour day. In contrast, circadian rhythms complete one cycle daily, while infradian rhythms such as the human menstrual cycle have periods longer than ...
rhythms such as metabolic, hormonal, CNS electrical, or neurotransmitter rhythms.
Recent research has influenced the design of spacecraft
A spacecraft is a vehicle or machine designed to fly in outer space. A type of artificial satellite, spacecraft are used for a variety of purposes, including communications, Earth observation, meteorology, navigation, space colonization, p ...
environments, as systems that mimic the light–dark cycle have been found to be highly beneficial to astronauts. Light therapy
Light therapy, also called phototherapy or bright light therapy is intentional daily exposure to direct sunlight or similar-intensity artificial light in order to treat medical disorders, especially seasonal affective disorder (SAD) and circadi ...
has been trialed as a treatment for sleep disorders.
Arctic animals
Norwegian researchers at the University of Tromsø
The University of Tromsø – The Arctic University of Norway (Norwegian: ''Universitetet i Tromsø – Norges arktiske universitet''; Northern Sami: ''Romssa universitehta – Norgga árktalaš universitehta'') is a state university in Norway an ...
have shown that some Arctic animals (e.g., ptarmigan
''Lagopus'' is a small genus of birds in the grouse subfamily commonly known as ptarmigans (). The genus contains three living species with numerous described subspecies, all living in tundra or cold upland areas.
Taxonomy and etymology
The ge ...
, reindeer
Reindeer (in North American English, known as caribou if wild and ''reindeer'' if domesticated) are deer in the genus ''Rangifer''. For the last few decades, reindeer were assigned to one species, ''Rangifer tarandus'', with about 10 subspe ...
) 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
Svalbard ( , ), also known as Spitsbergen, or Spitzbergen, is a Norwegian archipelago in the Arctic Ocean. North of mainland Europe, it is about midway between the northern coast of Norway and the North Pole. The islands of the group range ...
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.
A 2006 study in northern Alaska found that day-living ground squirrel
Ground squirrels are members of the squirrel family of rodents (Sciuridae), which generally live on or in the ground, rather than trees. The term is most often used for the medium-sized ground squirrels, as the larger ones are more commonly known ...
s and nocturnal porcupine
Porcupines are large rodents with coats of sharp spines, or quills, that protect them against predation. The term covers two families of animals: the Old World porcupines of family Hystricidae, and the New World porcupines of family, Erethizont ...
s 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.
Butterfly and moth
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. Circadian rhythm is also known to control mating behavior in certain moth species such as ''Spodoptera littoralis
''Spodoptera littoralis'', also referred to as the African cotton leafworm or Egyptian cotton leafworm or Mediterranean brocade, is a species of moth in the family Noctuidae. ''S. littoralis'' is found widely in Africa, Mediterranean Europe and ...
'', where females produce specific pheromone
A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...
that attracts and resets the male circadian rhythm to induce mating at night.
In plants
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, growth, germination, stomatal/gas exchange, enzyme activity, photosynthetic activity, and fragrance emission, among others. 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. 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 cryptochrome
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...
s. One phytochrome, phyA, is the main phytochrome in seedlings grown in the dark but rapidly degrades in light to produce Cry1. Phytochromes B–E are more stable with , 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.[
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.] 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
Timing of CAB expression 1 is a protein that in ''Arabidopsis thaliana'' is encoded by the TOC1 gene. TOC1 is also known as two-component response regulator-like APRR1.
TOC1 was the first plant gene that, when mutated, yielded a circadian phen ...
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
Timing of CAB expression 1 is a protein that in ''Arabidopsis thaliana'' is encoded by the TOC1 gene. TOC1 is also known as two-component response regulator-like APRR1.
TOC1 was the first plant gene that, when mutated, yielded a circadian phen ...
functions and interactions suggest a reframing of the plant circadian clock as a triple negative-component repressilator The repressilator is a genetic regulatory network consisting of at least one feedback loop with at least three genes, each expressing a protein that represses the next gene in the loop. In biological research, repressilators have been used to build ...
model rather than the positive/negative-element feedback loop characterizing the clock in mammals.
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.
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. Researchers came to this conclusion by performing experiments on three different varieties of ''Arabidopsis thaliana
''Arabidopsis thaliana'', the thale cress, mouse-ear cress or arabidopsis, is a small flowering plant native to Eurasia and Africa. ''A. thaliana'' is considered a weed; it is found along the shoulders of roads and in disturbed land.
A winter a ...
''. 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
Chlorophyll (also chlorophyl) is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words , ("pale green") and , ("leaf"). Chlorophyll allow plants to a ...
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'' 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.
According to the metabolic dawn hypothesis, sugars produced by photosynthesis have potential to help regulate the circadian rhythm and certain photosynthetic and metabolic pathways. As the sun rises, more light becomes available, which normally allows more photosynthesis to occur. The sugars produced by photosynthesis repress PRR7. 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.
In ''Drosophila''
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
A pupa ( la, pupa, "doll"; plural: ''pupae'') is the life stage of some insects undergoing transformation between immature and mature stages. Insects that go through a pupal stage are holometabolous: they go through four distinct stages in their ...
) from the pupa, and the other during mating. 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.
''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. 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. 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.
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.
PER-TIM model
This protein model was developed based on the oscillations of the PER and TIM proteins in the ''Drosophila''. It is based on its predecessor, the PER model where it was explained how the PER gene and its protein influence the biological clock. 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. 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.
In mammals
The primary circadian clock
A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...
in mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s is located in the suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
(or nuclei) (SCN), a pair of distinct groups of cells located in the hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
. 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
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
of the eye contains "classical" photoreceptors (" rods" and "cones
A cone is a three-dimensional geometric shape that tapers smoothly from a flat base (frequently, though not necessarily, circular) to a point called the apex or vertex.
A cone is formed by a set of line segments, half-lines, or lines conn ...
"), which are used for conventional vision. But the retina also contains specialized ganglion cell
{{stack,
A ganglion cell is a cell found in a ganglion. Examples of ganglion cells include:
* Retinal ganglion cell (RGC) found in the ganglion cell layer of the retina
* Cells that reside in the adrenal medulla, where they are involved in the ...
s 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.
These cells contain the photopigment melanopsin
Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene ''Opn4''. In the mammalian retina, there are two additional categories of opsins, both involved in the for ...
and their signals follow a pathway called the retinohypothalamic tract
In neuroanatomy, the retinohypothalamic tract (RHT) is a photic neural input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells (ipRGC), whi ...
, leading to the SCN. If cells from the SCN are removed and cultured, they maintain their own rhythm in the absence of external cues.
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
The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...
, a tiny structure shaped like a pine cone
A conifer cone (in formal botanical usage: strobilus, plural strobili) is a seed-bearing organ on gymnosperm plants. It is usually woody, ovoid to globular, including scales and bracts arranged around a central axis, especially in conifers a ...
and located on the epithalamus
The epithalamus is a posterior (dorsal) segment of the diencephalon. The epithalamus includes the habenular nuclei and their interconnecting fibers, the habenular commissure, the stria medullaris and the pineal gland.
Functions
The function of ...
. In response, the pineal secretes the hormone melatonin
Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.
In vertebrates ...
. 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.
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.
Humans
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. 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. A more stringent study conducted in 1999 by Harvard University
Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...
estimated the natural human rhythm to be closer to 24 hours and 11 minutes: much closer to the solar day
A synodic day (or synodic rotation period or solar day) is the period for a celestial object to rotate once in relation to the star it is orbiting, and is the basis of solar time.
The synodic day is distinguished from the sidereal day, which is ...
. 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). 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.
Biological markers and effects
The classic phase markers for measuring the timing of a mammal's circadian rhythm are:
* melatonin
Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle.
In vertebrates ...
secretion by the pineal gland
The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...
,
* core body temperature
Normal human body-temperature (normothermia, euthermia) is the typical temperature range found in humans. The normal human body temperature range is typically stated as .
Human body temperature varies. It depends on sex, age, time of day, exert ...
minimum, and
* plasma level of cortisol
Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone.
It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...
.
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 chronotype
A chronotype is the behavioral manifestation of underlying circadian rhythm's myriad of physical processes. A person's chronotype is the propensity for the individual to sleep at a particular time during a 24-hour period. ''Eveningness'' (delayed ...
s, 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. 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
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
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
Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...
and many cellular processes "including oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
, cell metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
, immune and inflammatory responses, epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
modification, hypoxia/hyperoxia
Hyperoxia occurs when cells, tissues and organs are exposed to an excess supply of oxygen (O2) or higher than normal partial pressure of oxygen.
In medicine, it refers to excessive oxygen in the lungs or other body tissues, which can be caused ...
response pathways, endoplasmic reticular stress, autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
, and regulation of the stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
environment." 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.
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.
Outside the "master clock"
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." For example, these clocks, called peripheral oscillators, have been found in the adrenal gland, oesophagus
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
, lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of th ...
, liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
, spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
, and skin. There is also some evidence that the olfactory bulb and prostate may experience oscillations, at least when cultured.
Though oscillators in the skin respond to light, a systemic influence has not been proven. In addition, many oscillators, such as liver cells
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, bi ...
, for example, have been shown to respond to inputs other than light, such as feeding.
Light and the biological clock
Light resets the biological clock in accordance with the phase response curve
A phase response curve (PRC) illustrates the transient change (phase response) in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received. PRCs are used in various fields; examples of biolog ...
(PRC). Depending on the timing, light can advance or delay the circadian rhythm. Both the PRC and the required illuminance
In photometry, illuminance is the total luminous flux incident on a surface, per unit area. It is a measure of how much the incident light illuminates the surface, wavelength-weighted by the luminosity function to correlate with human brightness ...
vary from species to species, and lower light levels are required to reset the clocks in nocturnal
Nocturnality is an animal behavior characterized by being active during the night and sleeping during the day. The common adjective is "nocturnal", versus diurnal meaning the opposite.
Nocturnal creatures generally have highly developed sens ...
rodents than in humans.
Enforced longer or shorter cycles
Various studies on humans have made use of enforced sleep/wake cycles strongly different from 24 hours, such as those conducted by Nathaniel Kleitman
Nathaniel Kleitman (April 26, 1895 – August 13, 1999) was an American physiologist and sleep researcher who served as Professor Emeritus in Physiology at the University of Chicago. He is recognized as the father of modern sleep research, an ...
in 1938 (28 hours) and Derk-Jan Dijk and Charles Czeisler
Charles A. Czeisler (born 1952) is an American physician and sleep researcher.Czeisler, Charles A. E-mail interview. 24 April 2013. He is a researcher and author in the fields of both circadian rhythms and sleep medicine.
Background and educati ...
in the 1990s (20 hours). Because people with a normal (typical) circadian clock
A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase (waves), phase and is synchronized with solar time.
Such a clock's ''in vivo'' period is necessarily almost exactly 24 hours (the earth's curre ...
cannot entrain to such abnormal day/night rhythms, 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
In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages.
Sleep latency studies
Pioneering Stanford Univers ...
and other functions - both physiological, behavioral, and cognitive.
Studies also show that ''Cyclosa turbinata
''Cyclosa turbinata'' is a species of orb weaver belonging to the family of spiders known as Araneidae. It is found in a range from the United States to Panama, West Indies, Galapagos Islands, and has been introduced into Hawaii.
Geographic Loc ...
'' 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.
Human health
Foundation of circadian medicine
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. This is leading to the development of an entirely new field of medicine, termed Circadian Medicine. Pioneering research reveals that Circadian Medicine can lead to longer and healthier lives. For example: 1) "Circadian Lighting" or reducing adverse light at night in hospitals may improve patient outcomes post-myocardial infarction (heart attack). 2) "Circadian Chronotherapy" or timing of medications can reduce adverse cardiac remodeling in patients with heart disease. 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. 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. Importantly, for rational translation of the most promising Circadian Medicine therapies to clinical practice, it is imperative that we understand how it helps treats disease in both biological sexes.
Relationship with cardiovascular disease
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. 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, and by studying shift workers.
Circadian desynchrony
Subsequent 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 power nap or cat nap is a short sleep that terminates before deep sleep (slow-wave sleep; SWS). A power nap is intended to quickly revitalize the sleeper.
Cornell University social psychologist James Maas coined the term. A power nap combine ...
, a short period of sleep during the day, can reduce stress and may improve productivity without any measurable effect on normal circadian rhythms. Circadian rhythms also play a part in the reticular activating system
The reticular formation is a set of interconnected nuclei that are located throughout the brainstem. It is not anatomically well defined, because it includes neurons located in different parts of the brain. The neurons of the reticular formatio ...
, which is crucial for maintaining a state of consciousness. A reversal in the sleep–wake cycle may be a sign or complication of uremia
Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess of amino acid and protein metabolism end products, such as urea and creatinine, in the blood that would be nor ...
, azotemia
Azotemia (''azot'', "nitrogen" + '' -emia'', "blood condition") is a medical condition characterized by abnormally high levels of nitrogen-containing compounds (such as urea, creatinine, various body waste compounds, and other nitrogen-rich compou ...
or acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are cla ...
. Studies have also helped elucidate how light has a direct effect
In European Union law, direct effect is the principle that Union law may, if appropriately framed, confer rights on individuals which the courts of member states of the European Union are bound to recognise and enforce.
Direct effect is not ex ...
on human health through its influence on the circadian biology.
Indoor lighting
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. Animal studies on the effects of light in laboratory conditions have until recently considered light intensity (irradiance In radiometry, irradiance is the radiant flux ''received'' by a ''surface'' per unit area. The SI unit of irradiance is the watt per square metre (W⋅m−2). The CGS unit erg per square centimetre per second (erg⋅cm−2⋅s−1) is often used ...
) but not color, which can be shown to "act as an essential regulator of biological timing in more natural settings".
Obesity and diabetes
Obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
and diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
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) might play a role in the development of metabolic disorders.
Shift work
Shift work is an employment practice designed to make use of, or provide service across, all 24 hours of the clock each day of the week (often abbreviated as '' 24/7''). The practice typically sees the day divided into shifts, set periods of ...
or chronic jet lag
Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. fr ...
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. In humans, shift work that favors irregular eating times is associated with altered insulin sensitivity and higher body mass. Shift work also leads to increased metabolic risks for cardio-metabolic syndrome, hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, and inflammation.[ ]
Airline pilots and cabin crew
Due to the work nature 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
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
. The NTSB
The National Transportation Safety Board (NTSB) is an independent U.S. government investigative agency responsible for civil transportation accident investigation. In this role, the NTSB investigates and reports on aviation accidents and incid ...
cites this as contributing to many accidents, and has conducted several research studies in order to find methods of combating fatigue in pilots.
Disruption
Disruption to rhythms usually has a negative effect. Many travelers have experienced the condition known as jet lag
Jet lag is a physiological condition that results from alterations to the body's circadian rhythms caused by rapid long-distance trans-meridian (east–west or west–east) travel. For example, someone flying from New York to London, i.e. fr ...
, with its associated symptoms of fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, disorientation
Orientation is a function of the mind involving awareness of three dimensions: time, Location (geography), place and person. Problems with orientation lead to ''dis''orientation, and can be due to various conditions, from delirium to Substance int ...
and insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
.
A number of other disorders, such as bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
and some sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
s such as delayed sleep phase disorder
Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a delaying of a person's circadian rhythm (biological clock) compared to those of societal norms. The diso ...
(DSPD), are associated with irregular or pathological functioning of circadian rhythms.
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. Blue LED lighting suppresses melatonin production five times more than the orange-yellow high-pressure sodium (HPS) light; a metal halide lamp
A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typicall ...
, which is white light, suppresses melatonin at a rate more than three times greater than HPS. Depression symptoms from long term nighttime light exposure can be undone by returning to a normal cycle.
Effect of drugs
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.
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 chooses to stop using drugs and alcohol, the circadian rhythm continues to be disrupted.[
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
The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...
may significantly influence the effects produced by drugs such as cocaine
Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...
. Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.
Society and culture
In 2017, Jeffrey C. Hall, Michael W. Young
Michael Warren Young (born March 28, 1949) is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within ''Drosophila melanogaster''.
At Rock ...
, and Michael Rosbash
Michael Morris Rosbash (born March 7, 1944) is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the ...
were awarded Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
"for their discoveries of molecular mechanisms controlling the circadian rhythm".
Circadian rhythms was taken as an example of scientific knowledge being transferred into the public sphere.
See also
* Actigraphy (also known as actimetry)
* ARNTL
Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) or brain and muscle ARNT-Like 1 (BMAL1) is a protein that in humans is encoded by the gene on chromosome 11, region p15.3. It's also known as ''BMAL1'', ''MOP3'', and, less c ...
* ARNTL2
Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Mop9, Bmal2, Clif, or Arntl2, is a gene.
Arntl2 is a paralog to Arntl, which are both homologs of the Drosophila Cycle. Homologs were also isolated in fish, birds and mammals s ...
* Bacterial circadian rhythms Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three characteristics: (a) in constant conditions (i.e. constant temperature and either constant light or constant darkness ) the ...
* Circadian rhythm sleep disorders
Circadian rhythm sleep disorders (CRSD), also known as circadian rhythm sleep-wake disorders (CRSWD), are a family of sleep disorders which affect the timing of sleep. CRSDs arise from a persistent pattern of sleep/wake disturbances that can be ...
, such as
** Advanced sleep phase disorder
Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early mor ...
** Delayed sleep phase disorder
Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is a delaying of a person's circadian rhythm (biological clock) compared to those of societal norms. The diso ...
** Non-24-hour sleep–wake disorder
Non-24-hour sleep–wake disorder (non-24 or N24SWD) is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising ..daily delays in sleep onset and wake times in an individual livin ...
* Chronobiology
Chronobiology is a field of biology that examines timing processes, including periodic (cyclic) phenomena in living organisms, such as their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobi ...
* CLOCK
A clock or a timepiece is a device used to measure and indicate time. The clock is one of the oldest human inventions, meeting the need to measure intervals of time shorter than the natural units such as the day, the lunar month and the ...
* Circasemidian rhythm In chronobiology, a circasemidian rhythm is a physiological arousal cycle that peaks twice in a 24-hour day. It may also be called the semicircadian rhythm . Numerous studies have demonstrated that human circadian rhythms in many measures of perform ...
* Circaseptan
A circaseptan rhythm is a cycle consisting of approximately 7 days in which many biological processes of life, such as cellular immune system activity, resolve.
See also
*Circadian rhythm
*Chronobiology
Chronobiology is a field of biology th ...
, 7-day biological cycle
* Cryptochrome
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...
* CRY1
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...
and CRY2
Cryptochromes (from the Greek κρυπτός χρώμα, "hidden colour") are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields i ...
: the cryptochrome family genes
* Diurnal cycle
A diurnal cycle (or diel cycle) is any pattern that recurs every 24 hours as a result of one full rotation of the planet Earth around its axis. Earth's rotation causes surface temperature fluctuations throughout the day and night, as well as w ...
* Light effects on circadian rhythm
Light effects on circadian rhythm are the effects that light has on circadian rhythm.
Most animals and other organisms have "built-in clocks" in their brains that regulate the timing of biological processes and daily behavior. These "clocks" are ...
* Light in school buildings
* PER1
The PER1 gene encodes the period circadian protein homolog 1 protein in humans.
Function
The PER1 protein is important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer. This gene is a memb ...
, PER2
PER2 is a protein in mammals encoded by the ''PER2'' gene. ''PER2'' is noted for its major role in circadian rhythms.
Discovery
The ''per ''gene'' ''was first discovered using forward genetics in '' Drosophilla melanogaster'' in 1971. Mammalia ...
, and PER3
The PER3 gene encodes the period circadian protein homolog 3 protein in humans. PER3 is a paralog to the PER1 and PER2 genes. It is a circadian gene associate with delayed sleep phase syndrome in humans.
History
The Per3 gene was independently ...
: the period family genes
* Photosensitive ganglion cell
Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence ...
: part of the eye which is involved in regulating circadian rhythm.
* Polyphasic sleep
Biphasic sleep (or ''diphasic'', ''bifurcated'', or bimodal sleep) is the practice of sleeping during two periods over the course of 24 hours, while polyphasic sleep refers to sleeping multiple times—usually more than two. Each of these is in ...
* Rev-ErbA alpha
Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the '' ...
* Segmented sleep
Biphasic sleep (or ''diphasic'', ''bifurcated'', or bimodal sleep) is the practice of sleeping during two periods over the course of 24 hours, while polyphasic sleep refers to sleeping multiple times—usually more than two. Each of these is in ...
* Sleep architecture
Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a d ...
(sleep in humans)
* Sleep in non-human animals
* Stefania Follini
Stefania Follini (born 16 August 1961) is an Italian interior designer. She is known for being involved in a 1989 experiment on circadian rhythms, in which she voluntarily isolated herself for four months in an underground room thirty feet down a ...
* Ultradian rhythm
In chronobiology, an ultradian rhythm is a recurrent period or cycle repeated throughout a 24-hour day. In contrast, circadian rhythms complete one cycle daily, while infradian rhythms such as the human menstrual cycle have periods longer than a ...
References
Further reading
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External links
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{{DEFAULTSORT:Circadian Rhythm
Sleep
Biology of bipolar disorder
Plant cognition