Circadian rhythm

A circadian rhythm (/sərˈkeɪdiən/), or circadian cycle, is a natural oscillation that repeats roughly
every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e.,
endogenous) and responds to the environment (is entrained by the environment). Circadian rhythms
are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological
processes so they occur at the correct time to maximize the fitness of an individual. Circadian
rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is
evidence that they evolved independently in each of these kingdoms of life.[1][2]

The term circadian comes from the Latin circa, Circadian rhythm
meaning "around", 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.[3] Features of the human circadian biological
clock
Although circadian rhythms are endogenous, they
are adjusted to the local environment by external Pronunciation /sərˈkeɪdiən/

cues called zeitgebers (from German Zeitgeber Frequency Repeats roughly

(German: [ˈtsaɪtˌɡeːbɐ]; lit. 'time giver')), which every 24 hours
include light, temperature and redox cycles. In
clinical settings, an abnormal circadian rhythm in humans is known as a circadian rhythm sleep
disorder.[4]

History

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."[5] 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.[6]
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.[7]

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.[8][9]

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.[10] 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.[11]

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.[12] The existence of circadian rhythm
was independently discovered in fruit flies in 1935 by two German zoologists, Hans Kalmus and
Erwin Bünning.[13][14]

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.[15][14]

The term circadian was coined by Franz Halberg in 1959.[16] According to Halberg's original
definition:

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.[17][18]

In 1977, the International Committee on Nomenclature of the International Society for

Chronobiology formally adopted the definition:
 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.[19]

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.[20]
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.[21][22] 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.[23][24] 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.[25]

Joseph Takahashi discovered the first mammalian circadian clock mutation (clockΔ19) using mice
in 1994.[26][27] 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.[28][29]

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.[30][31]

Criteria

To be called circadian, a biological rhythm must meet these three general criteria:[32]

1. 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
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.

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 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.

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.[33] This is suggested by the maintenance (heritability) of
circadian rhythms in fruit flies after several hundred generations in constant laboratory
conditions,[34] 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.[35][36]

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.[37] 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.[1][4] 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)[38] 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.

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.[39]

It is now known that the molecular circadian clock can function within a single cell. That is, it is cell-
autonomous.[40] This was shown by Gene Block in isolated mollusk basal retinal neurons (BRNs).[41]
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.[42][43]

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 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.[44]
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.[45] 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.[46] 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.[47][48]

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 period, is shorter or longer
than 24 hours. The environmental cues that reset the rhythms each day are called zeitgebers.[49]
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.[50]

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.[51]

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.[52] Light therapy has been
trialed as a treatment for sleep disorders.

Arctic animals

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.[53]

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.[54]

Butterflies and moths

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.[55][56] 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.[57]

In plants

Sleeping tree by day and night

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.[58] 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.[59] 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.[60] Phytochromes B–E are more stable with 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.[58][59]

Graph showing timeseries data from

bioluminescence imaging 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.[61][62] 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,[59] 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.[63]

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.[64]

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.[65] 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.[65] 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.[65]

The Arabidopsis with the 24-hour circadian cycle was grown in three different environments.[65] 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).[65] 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.[65] 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.[65] 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.[65]

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.[65] In this study, it was also found that the genes that
help to control chlorophyll peaked a few hours after dawn.[65] This appears to be consistent with the
proposed phenomenon known as metabolic dawn.[66]

According to the metabolic dawn hypothesis, sugars produced by photosynthesis have potential to
help regulate the circadian rhythm and certain photosynthetic and metabolic pathways.[66][67] As the
sun rises, more light becomes available, which normally allows more photosynthesis to occur.[66]
The sugars produced by photosynthesis repress PRR7.[68] This repression of PRR7 then leads to the
increased expression of CCA1.[68] On the other hand, decreased photosynthetic sugar levels
increase PRR7 expression and decrease CCA1 expression.[66] This feedback loop between CCA1
and PRR7 is what is proposed to cause metabolic dawn.[66][69]

In Drosophila

Key centers of the mammalian and

Drosophila brains (A) and the
circadian system in Drosophila (B)

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.[70] 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.[71]

Molecular interactions of clock genes

and proteins during Drosophila
circadian rhythm

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.[72] 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.[73][74] 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.[75]

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.[76]

PER-TIM model

This protein model was developed based on the oscillations of the PER and TIM proteins in the
Drosophila.[77] It is based on its predecessor, the PER model where it was explained how the PER
gene and its protein influence the biological clock.[78] 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.[79][77] 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.[77] 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.[79]

In mammals

A variation of an eskinogram 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.[80]

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.[81]

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.[82] 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.[83]

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.[84]

Humans

When eyes receive light from the sun, the pineal

gland's production of melatonin is inhibited, and the
hormones produced keep the human awake. When
the eyes do not receive light, melatonin is produced
in the pineal gland and the human becomes tired.

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.[85] 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.[86] 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.[87] 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).[88] 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.[88]
Biological markers and effects

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

melatonin secretion by the pineal gland,[89]

core body temperature minimum,[89] and

plasma level of cortisol.[90]

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.[91] 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.[89] 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,[92] epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular
stress, autophagy, and regulation of the stem cell environment."[93] 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.[94]

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.[95]
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".[96]
For example, these clocks, called peripheral oscillators, have been found in the adrenal gland,
oesophagus, lungs, liver, pancreas, spleen, thymus, and skin.[97][98][99] There is also some evidence
that the olfactory bulb[100] and prostate[101] may experience oscillations, at least when cultured.

Though oscillators in the skin respond to light, a systemic influence has not been proven.[102] In
addition, many oscillators, such as liver cells, for example, have been shown to respond to inputs
other than light, such as feeding.[103]

Light and the biological clock

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.[104]

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 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,[105] 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.[106][107][108][109][110]

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.
 How humans can optimize their
circadian rhythm in terms of ability to
achieve proper sleep

Human health

A short nap during the day does not

affect circadian rhythms.

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.[111][112][113][114] 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.[115] 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.[116] 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.[117][118][119][120]
Causes of disruption to circadian rhythms

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.[121] 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".[122]

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.[123] Depression symptoms from long term nighttime
light exposure can be undone by returning to a normal cycle.[124]

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. The NTSB cites this as contributing to many accidents,[125] and has conducted
several research studies in order to find methods of combating fatigue in pilots.[126]

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.[127]

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.[127]

The stabilization of sleep and the circadian rhythm might possibly help to reduce the vulnerability to
addiction and reduce the chances of relapse.[127]
Circadian rhythms and clock genes expressed in brain regions outside the suprachiasmatic nucleus
may significantly influence the effects produced by drugs such as cocaine. Moreover, genetic
manipulations of clock genes profoundly affect cocaine's actions.[128]

Consequences of disruption to circadian rhythms

Disruption

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.[129]

A number of other disorders, such as bipolar disorder and some sleep disorders such as delayed
sleep phase disorder (DSPD), are associated with irregular or pathological functioning of circadian
rhythms.[130][131]

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.[132][133]

Studies have shown that maintaining normal sleep and circadian rhythms is important for many
aspects of brain and health.[132] 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.[134][135][136] Circadian rhythms also play a part in the
reticular activating system, which is crucial for maintaining a state of consciousness. A reversal in
the sleep–wake cycle may be a sign or complication of uremia,[137] azotemia or acute kidney
injury.[138][139] Studies have also helped elucidate how light has a direct effect on human health
through its influence on the circadian biology.[140]

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.[141] 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.[141] The adverse effects of circadian misalignment
on human physiology has been studied in the laboratory using a misalignment protocol,[142][143] and
by studying shift workers.[111][144][145] 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.[145] 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.[145][146] Shift work and the
resulting circadian misalignment is also associated with hypertension.[147]

Obesity and diabetes

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.[132]

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.[148][146] In humans, shift work that favours irregular
eating times is associated with altered insulin sensitivity, diabetes and higher body
mass.[147][146][149]

Cognitive effects

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.[150]
Increased risk of dementia is associated with chronic night shift workers compared to day shift
workers, particularly for individuals over 50 years old.[151][152][153]

Society and culture

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".[154][155]

Circadian rhythms was taken as an example of scientific knowledge being transferred into the public
sphere.[156]

See also

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
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Further reading

Aschoff J, ed. (1965). Circadian Clocks. Amsterdam: North Holland Press.

Avivi A, Albrecht U, Oster H, Joel A, Beiles A, Nevo E (November 2001). "Biological clock in total
darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat" (https://www.ncb
i.nlm.nih.gov/pmc/articles/PMC61113) . Proceedings of the National Academy of Sciences of the
United States of America. 98 (24): 13751–6. Bibcode:2001PNAS...9813751A (https://ui.adsabs.ha
rvard.edu/abs/2001PNAS...9813751A) . doi:10.1073/pnas.181484498 (https://doi.org/10.107
3%2Fpnas.181484498) . PMC 61113 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC61113) .
PMID 11707566 (https://pubmed.ncbi.nlm.nih.gov/11707566) .

Avivi A, Oster H, Joel A, Beiles A, Albrecht U, Nevo E (September 2002). "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" (https://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC129335) . Proceedings of the National Academy of Sciences of the United States of
America. 99 (18): 11718–23. Bibcode:2002PNAS...9911718A (https://ui.adsabs.harvard.edu/abs/
2002PNAS...9911718A) . doi:10.1073/pnas.182423299 (https://doi.org/10.1073%2Fpnas.18242
3299) . PMC 129335 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129335) .
PMID 12193657 (https://pubmed.ncbi.nlm.nih.gov/12193657) .

Li D, Ma S, Guo D, Cheng T, Li H, Tian Y, et al. (October 2016). "Environmental Circadian Disruption

Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After
Traumatic Brain Injury" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967018) . Cellular and
Molecular Neurobiology. 36 (7): 1045–55. doi:10.1007/s10571-015-0295-2 (https://doi.org/10.100
7%2Fs10571-015-0295-2) . PMC 4967018 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC496
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Ditty JL, Williams SB, Golden SS (2003). "A cyanobacterial circadian timing mechanism". Annual
Review of Genetics. 37: 513–43. doi:10.1146/annurev.genet.37.110801.142716 (https://doi.org/1
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v/14616072) . S2CID 36703896 (https://api.semanticscholar.org/CorpusID:36703896) .

Dunlap JC, Loros J, DeCoursey PJ (2003). Chronobiology: Biological Timekeeping (https://archive.o

rg/details/chronobiologybio0000unse) . Sunderland: Sinauer. ISBN 978-0-87893-149-1.

Dvornyk V, Vinogradova O, Nevo E (March 2003). "Origin and evolution of circadian clock genes in
prokaryotes" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151369) . Proceedings of the
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ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC151369) . PMID 12604787 (https://pubmed.ncbi.
nlm.nih.gov/12604787) .
 Koukkari WL, Sothern RB (2006). Introducing Biological Rhythms. New York: Springer.

Martino T, Arab S, Straume M, Belsham DD, Tata N, Cai F, et al. (April 2004). "Day/night rhythms in
gene expression of the normal murine heart". Journal of Molecular Medicine. 82 (4): 256–64.
doi:10.1007/s00109-003-0520-1 (https://doi.org/10.1007%2Fs00109-003-0520-1) .
PMID 14985853 (https://pubmed.ncbi.nlm.nih.gov/14985853) . S2CID 871822 (https://api.sema
nticscholar.org/CorpusID:871822) .

Refinetti R (2006). Circadian Physiology (2nd ed.). Boca Raton: CRC Press.

Takahashi JS, Zatz M (September 1982). "Regulation of circadian rhythmicity". Science. 217
(4565): 1104–11. Bibcode:1982Sci...217.1104T (https://ui.adsabs.harvard.edu/abs/1982Sci...21
7.1104T) . doi:10.1126/science.6287576 (https://doi.org/10.1126%2Fscience.6287576) .
PMID 6287576 (https://pubmed.ncbi.nlm.nih.gov/6287576) .

Tomita J, Nakajima M, Kondo T, Iwasaki H (January 2005). "No transcription-translation feedback

in circadian rhythm of KaiC phosphorylation" (https://doi.org/10.1126%2Fscience.1102540) .
Science. 307 (5707): 251–4. Bibcode:2005Sci...307..251T (https://ui.adsabs.harvard.edu/abs/200
5Sci...307..251T) . doi:10.1126/science.1102540 (https://doi.org/10.1126%2Fscience.110254
0) . PMID 15550625 (https://pubmed.ncbi.nlm.nih.gov/15550625) . S2CID 9447128 (https://ap
i.semanticscholar.org/CorpusID:9447128) .

Moore-Ede MC, Sulzman FM, Fuller CA (1982). The Clocks that Time Us: Physiology of the
Circadian Timing System (https://archive.org/details/clocksthattimeus0000moor) . Cambridge,
Massachusetts: Harvard University Press. ISBN 978-0-674-13581-9.

External links

Circadian rhythm (https://curlie.org/Health/Conditions_and_Diseases/Sleep_Disorders/Biological

_Rhythms) at Curlie