Circadian rhythm
Overview
 
A circadian rhythm, popularly referred to as body clock, is an endogenously driven (non-reliant on environmental cues), roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria (see bacterial circadian rhythms
Bacterial circadian rhythms
Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three characteristics: in constant conditions Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three...

). The term circadian comes from the Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

 circa
Circa
Circa , usually abbreviated c. or ca. , means "approximately" in the English language, usually referring to a date...

, meaning "around", and diem or dies, meaning "day".
Encyclopedia
A circadian rhythm, popularly referred to as body clock, is an endogenously driven (non-reliant on environmental cues), roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria (see bacterial circadian rhythms
Bacterial circadian rhythms
Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three characteristics: in constant conditions Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three...

). The term circadian comes from the Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

 circa
Circa
Circa , usually abbreviated c. or ca. , means "approximately" in the English language, usually referring to a date...

, meaning "around", and diem or dies, meaning "day". The formal study of biological temporal rhythms such as daily, tidal, weekly, seasonal, and annual rhythms is called chronobiology
Chronobiology
Chronobiology is a field of biology that examines periodic phenomena in living organisms and their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobiology comes from the ancient Greek χρόνος , and biology, which pertains to the study, or science,...

. Although circadian rhythms are endogenous ("built-in", self-sustained), they are adjusted (entrained
Entrainment (chronobiology)
Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...

) to the environment by external cues called zeitgeber
Zeitgeber
Zeitgeber is any exogenous cue that synchronizes an organism's endogenous time-keeping system to the earth's 24-hour light/dark cycle. The strongest zeitgeber, for both plants and animals, is light...

s, the primary one of which is daylight
Daylight
Daylight or the light of day is the combination of all direct and indirect sunlight outdoors during the daytime. This includes direct sunlight, diffuse sky radiation, and both of these reflected from the Earth and terrestrial objects. Sunlight scattered or reflected from objects in outer space is...

.

History

The earliest known account of a circadian process dates from the 4th century BC, when Androsthenes, a ship captain serving under Alexander the Great, described diurnal leaf movements of the tamarind
Tamarind
Tamarind is a tree in the family Fabaceae. The genus Tamarindus is monotypic .-Origin:...

 tree.

The first recorded observation of an endogenous circadian oscillation
Circadian oscillator
Circadian oscillators are components of the biological clocks that regulate the activities of organisms in relation to environmental cycles and provide an internal temporal framework...

 was by the French scientist Jean-Jacques d'Ortous de Mairan
Jean-Jacques d'Ortous de Mairan
Jean-Jacques d'Ortous de Mairan , a French geophysicist, astronomer and most notably, chronobiologist, was born in the town of Béziers on November 26, 1678...

 in 1729. He noted that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica
Mimosa pudica
Mimosa pudica , is a creeping annual or perennial herb often grown for its curiosity value: the compound leaves fold inward and droop when touched or shaken, re-opening minutes later...

continued even when the plants were kept in constant darkness, in the first experiment to attempt to distinguish an endogenous clock from responses to daily stimuli.

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. 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. Ron Konopka
Ron Konopka
Ronald J. Konopka is a former 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...

 and Seymour Benzer
Seymour Benzer
Seymour Benzer 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 fields of molecular and behavioral genetics. He led a productive genetics research lab both at...

 isolated the first clock mutant in Drosophila in the early seventies and mapped the "period
Period (gene)
Period is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving...

" gene, the first discovered genetic component of a circadian clock. Joseph Takahashi
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 discovered the genetic basis for the mammalian...

 discovered the first mammalian 'clock gene' (CLOCK
CLOCK
Clock is a gene encoding a basic-helix-loop-helix-PAS transcription factor that affects both the persistence and period of circadian rhythms...

) using mice in 1994.

The term "circadian" was coined by Franz Halberg
Franz Halberg
Franz Halberg is a scientist and one of the founders of modern chronobiology. He first began his experiments in the 1940s and later founded the Chronobiology Laboratories at the University of Minnesota...

 in the late 1950s.

Criteria

To be called circadian, a biological rhythm must meet these four general criteria:
  1. The rhythms repeat once a day (they have a 24-hour period). In order to keep track of the time of day, a clock must be at the same point at the same time each day, i.e. repeat every 24 hours.
  2. The rhythms persist in the absence of external cues (endogenous). The rhythm persists in constant conditions with a period of about 24 hours. 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 in conditions without external periodic input.
  3. The rhythms can be adjusted to match the local time (entrainable). The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment
    Entrainment (chronobiology)
    Entrainment, within the study of chronobiology, occurs when rhythmic physiological or behavioral events match their period and phase to that of an environmental oscillation. A common example is the entrainment of circadian rhythms to the daily light–dark cycle, which ultimately is determined by...

    . The rationale for this criterion is to distinguish circadian rhythms from other imaginable endogenous 24-hour rhythms that are immune to resetting by external cues and, hence, do not serve the purpose of estimating the local time. Travel across time zone
    Time zone
    A time zone is a region on Earth that has a uniform standard time for legal, commercial, and social purposes. In order for the same clock time to always correspond to the same portion of the day as the Earth rotates , different places on the Earth need to have different clock times...

    s illustrates the ability of the human biological clock to adjust to the local time; a person will usually experience jet lag
    Jet lag
    Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...

     before entrainment of their circadian clock has brought it into sync with local time.
  4. The rhythms maintain circadian periodicity over a range of physiological temperatures (exhibit temperature compensation). Some organisms live at a broad range of temperatures, and the 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 a roughly 24-hour periodicity despite the changing kinetics, a property known as temperature compensation.

Origin

Photosensitive proteins and circadian rhythms are believed to have originated in the earliest cells, with the purpose of protecting the replicating of DNA from high ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...

 radiation during the daytime. As a result, replication was relegated to the dark. The fungus Neurospora
Neurospora
Neurospora is a genus of Ascomycete fungi. The genus name, meaning "nerve spore" refers to the characteristic striations on the spores that resemble axons....

, which exists today, retains this clock-regulated mechanism
Circadian oscillator
Circadian oscillators are components of the biological clocks that regulate the activities of organisms in relation to environmental cycles and provide an internal temporal framework...

.

Circadian rhythms allow organisms to anticipate and prepare for precise and regular environmental changes; they have great value in relation to the outside world. The 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 behavioural but not physiological circadian rhythms in quail.

The simplest known circadian clock is that of the prokaryotic cyanobacteria. Recent research has demonstrated that the circadian clock of Synechococcus elongatus can be reconstituted in vitro with just the three proteins of their central oscillator. This clock has been shown to sustain a 22-hour rhythm over several days upon the addition of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

. Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription/translation feedback mechanism.

A defect in the human homologue of the Drosophilla "period
Period (gene)
Period is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving...

" 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.

It is now known that the molecular circadian clock can function within a single cell; i.e., it is cell-autonomous. At the same time, different cells may communicate with each other resulting in a synchronised 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 synchronise the peripheral clocks of various organs. Thus, the information of the time of the day as relayed by the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...

s 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
* Brain Wave, a science fiction novel by Poul Anderson* a neural oscillation* a layman term for the electric fields measured by Electroencephalography...

 activity, hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 production, cell regeneration and other biological activities. In addition, photoperiodism
Photoperiodism
Photoperiodism is the physiological reaction of organisms to the length of day or night. It occurs in plants and animals.Photoperiodism can also be defined as the developmental responses of plants to the relative lengths of the light and dark periods...

, 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.

Impact 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 freerunning
Free-running sleep
Free-running sleep experiments can involve any organism which sleeps. Free-running sleep is sleep which is not adjusted, entrained, to the 24-hour cycle in nature nor to any artificial cycle. Such experiments are used in the study of circadian and other rhythms in biology...

 rhythm. Each "day", their sleep cycle is pushed back or forward, depending on whether their endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

 period is shorter or longer than 24 hours. The environmental cues that reset the rhythms each day are called zeitgeber
Zeitgeber
Zeitgeber is any exogenous cue that synchronizes an organism's endogenous time-keeping system to the earth's 24-hour light/dark cycle. The strongest zeitgeber, for both plants and animals, is light...

s
(from the German, "time-givers"). It is interesting to note that totally-blind subterranean mammals (e.g., blind mole rat
Blind mole rat
The genus Spalax contains the blind, fossorial, or subterranean mole rats, which are one of several types of rodents that are called mole rats. The hystricognath mole rats of the family Bathyergidae are completely unrelated, but some other forms are also in the family Spalacidae...

 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.

Freerunning 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, of course, 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
Ultradian
Ultradian rhythms are recurrent periods or cycles repeated throughout a 24-hour circadian day. In contrast, infradian rhythms, such as the human menstrual cycle, have periods longer than a day....

 rhythms such as metabolic, hormonal, CNS electrical, or neurotransmitter rhythms.

Recent research has influenced the design of spacecraft
Human spaceflight
Human spaceflight is spaceflight with humans on the spacecraft. When a spacecraft is manned, it can be piloted directly, as opposed to machine or robotic space probes and remotely-controlled satellites....

 environments, as systems that mimic the light–dark cycle have been found to be highly beneficial to astronauts.

Arctic animals

Norwegian researchers at the University of Tromsø
University of Tromsø
The University of Tromsø is the world's northernmost university. Located in the city of Tromsø, Norway, it was established in 1968, and opened in 1972. It is one of eight universities in Norway. The University of Tromsø is the largest research and educational institution in northern Norway...

 have shown that some Arctic animals (ptarmigan, reindeer
Reindeer
The reindeer , also known as the caribou in North America, is a deer from the Arctic and Subarctic, including both resident and migratory populations. While overall widespread and numerous, some of its subspecies are rare and one has already gone extinct.Reindeer vary considerably in color and size...

) 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
70th parallel north
The 70th parallel north is a circle of latitude that is 70 degrees north of the Earth's equatorial plane, in the Arctic. It crosses the Atlantic Ocean, Europe, Asia and North America, and passes through some of the southern seas of the Arctic Ocean....

 showed circadian rhythms in the autumn, winter, and spring, but not in the summer. Reindeer at 78 degrees North
78th parallel north
The 78th parallel north is a circle of latitude that is 78 degrees north of the Earth's equatorial plane, in the Arctic. It crosses the Atlantic Ocean, Europe, Asia, the Arctic Ocean and North America....

 showed such rhythms only 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.

However, another study in northern Alaska found that ground squirrel
Ground squirrel
The ground squirrels are members of the squirrel family of rodents 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 as marmots or prairie dogs, while the smaller and less...

s and porcupine
Porcupine
Porcupines are rodents with a coat of sharp spines, or quills, that defend or camouflage them from predators. They are indigenous to the Americas, southern Asia, and Africa. Porcupines are the third largest of the rodents, behind the capybara and the beaver. Most porcupines are about long, with...

s strictly maintained their circadian rhythms through 82 days and nights of sunshine. The researchers speculate that these two small mammals see that the apparent distance between the sun and the horizon is shortest once a day, and, thus, a sufficient signal to adjust by.

Butterfly migration

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.

In plants

Plant circadian rhythms tell the plant what season it is in and when to flower for the best chance of attracting insects to pollinate them and can include leaf movement, growth, germination, stomatal/gas exchange, enzyme activity, photosynthetic activity, and fragrance emission. Circadian rhythms occur as a biological rhythm with light, are endogenously generated and self sustaining, and are relatively constant over a range of ambient temperatures. Circadian rhythms feature a transcriptional feedback loop, a presence of PAS proteins, and several photoreceptors that fine-tune the clock to different light conditions. Anticipation of changes in the environment changes the physiological state that provides plants with an adaptive advantage. A better understanding of plant circadian rhythms has applications in agriculture such as helping farmers stagger crop harvests thus extending crop availability, and to secure against massive losses due to weather.

Clocks are set through signals such as light, temperature, and nutrient availability, so that the internal time matches the local time. Light is the signal and is sensed by a wide variety of photoreceptors. Red and blue light are absorbed through several phytochromes and cryptochromes. One phytochrome, phyA, is the main phytochrome in dark-grown seedlings, but rapidly degrades in light to produce Cry1. Phytochromes B–E are more stable with phyB the main phytochrome in light-grown seedlings. The cryptochrome (cry) gene is also a light-sensitive component of the circadian clock. 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 made of two genes: CCA1 (Circadian and Clock Associated 1) and LHY (Late Elongated Hypocotyl) that encode closely related MYB transcription factors that regulate circadian rhythms in Arabidopsis. When CCA1 and LHY are overexpressed (under constant light or dark conditions) plants become arrhythimcal and mRNA signals reduce contributing to a negative feedback loop. CCA1 and LHY expression oscillates and peaks in early morning while TOC1 oscillates and peaks in early evening. From past observations and studies, it is hypothesised that these three components model a negative feedback loop in which over-expressed CCA1 and LHY repress TOC1 and over-expressed TOC1 is a positive regulator CCA1 and LHY.

Biological clock in mammals

The primary circadian "clock" in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s is located in the suprachiasmatic nucleus
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...

 (or nuclei) (SCN), a pair of distinct groups of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 located in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

. 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
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...

 of the eye contains "classical" photoreceptors ("rods
Rod cell
Rod cells, or rods, are photoreceptor cells in the retina of the eye that can function in less intense light than can the other type of visual photoreceptor, cone cells. Named for their cylindrical shape, rods are concentrated at the outer edges of the retina and are used in peripheral vision. On...

" and "cones
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...

"), which are used for conventional vision. But the retina also contains specialized ganglion cell
Ganglion cell
A retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...

s which are directly photosensitive, and project directly to the SCN where they help in the entrainment of this master circadian clock.

These cells contain the photopigment melanopsin
Melanopsin
Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...

 and their signals follow a pathway called the retinohypothalamic tract
Retinohypothalamic tract
The retinohypothalamic tract is a photic input pathway involved in the circadian rhythms of mammals. The origin of the retinohypothalamic tract is the intrinsically photosensitive retinal ganglion cells , which contain the photopigment melanopsin...

, 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
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...

, a tiny structure shaped like a pine cone and located on the epithalamus
Epithalamus
The epithalamus is a dorsal posterior segment of the diencephalon which includes the habenula, the stria medullaris and the pineal body...

. In response, the pineal secretes the hormone melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...

. 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 recently shown that human subjects can at least be entrained to a 23.5-hour cycle and a 24.65-hour cycle (the latter being the natural solar day-night cycle on the planet Mars
Mars
Mars is the fourth planet from the Sun in the Solar System. The planet is named after the Roman god of war, Mars. It is often described as the "Red Planet", as the iron oxide prevalent on its surface gives it a reddish appearance...

).

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. These results became well-known.

More recent research has shown that: adults have a built-in day, which averages about 24 hours; indoor lighting does affect circadian rhythms; and most people attain their best-quality sleep during their chronotype
Chronotype
Chronotype is an attribute of animals, including human beings, reflecting at what time of the day their physical functions are active, change or reach a certain level...

-determined sleep periods. A study by Czeisler et al. at Harvard found the range for normal, healthy adults of all ages to be quite narrow: 24 hours and 11 minutes ± 16 minutes. The "clock" resets itself daily to the 24-hour cycle of the Earth's rotation.

Biological markers

The classic phase markers for measuring the timing of a mammal's circadian rhythm are:
  • melatonin
    Melatonin
    Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...

     secretion by the pineal gland
    Pineal gland
    The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...

  • core body temperature
  • plasma level of cortisol
    Cortisol
    Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

    .


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
Chronotype
Chronotype is an attribute of animals, including human beings, reflecting at what time of the day their physical functions are active, change or reach a certain level...

s.

Melatonin is absent from the system or undetectably low during daytime. Its onset in dim light, dim-light melatonin onset (DLMO), at about 21:00 (9 p.m.) can be measured in the blood or the saliva. Its major metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

 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. in Chicago in 2005 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 were more strongly correlated with the various phase markers than sleep onset. In addition, the declining phase of the melatonin levels was more reliable and stable than the termination of melatonin synthesis.

One method used for measuring melatonin offset is to analyse a sequence of urine samples throughout the morning for the presence of the melatonin metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

 6-sulphatoxymelatonin (aMT6s). Laberge et al. in Quebec in 1997 used this method in a study that confirmed the frequently found delayed circadian phase in healthy adolescents.

A third marker of the human pacemaker is the timing of the maximum plasma cortisol level. Klerman et al. in 2002 compared cortisol and temperature data to eight different analysis methods of plasma melatonin data, and found that "methods using plasma melatonin data may be considered more reliable than methods using CBT or cortisol data as an indicator of circadian phase in humans."

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". These clocks, called peripheral oscillators, are found in the oesophagus, lungs, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...

, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

, thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....

, and the skin. Though oscillators in the skin respond to light, a systemic influence has not been proven so far. There is also some evidence that the olfactory bulb and prostate may experience oscillations when cultured, suggesting that these structures may also be weak oscillators.

Furthermore, liver cells, for example, appear to respond to feeding rather than to light. Cells from many parts of the body appear to have freerunning rhythms.

Light and the biological clock

Light resets the biological clock in accordance with the phase response curve
Phase response curve
A phase response curve illustrates the transient change in the cycle period of an oscillation induced by a perturbation as a function of the phase at which it is received...

 (PRC). Depending on the timing, light can advance or delay the circadian rhythm. Both the PRC and the required illuminance
Illuminance
In photometry, illuminance is the total luminous flux incident on a surface, per unit area. It is a measure of the intensity of the incident light, wavelength-weighted by the luminosity function to correlate with human brightness perception. Similarly, luminous emittance is the luminous flux per...

 vary from species to species and lower light levels are required to reset the clocks in nocturnal rodents than in humans.

Lighting levels that affect the circadian rhythm in humans are higher than the levels usually used in artificial lighting in homes. According to some researchers the illumination intensity that excites the circadian system has to reach up to 1000 lux
Lux
The lux is the SI unit of illuminance and luminous emittance, measuring luminous flux per unit area. It is used in photometry as a measure of the intensity, as perceived by the human eye, of light that hits or passes through a surface...

 striking the retina.

In addition to light intensity, wavelength (or colour) of light is a factor in the entrainment of the body clock. Melanopsin
Melanopsin
Melanopsin is a photopigment found in specialized photosensitive ganglion cells of the retina that are involved in the regulation of circadian rhythms, pupillary light reflex, and other non-visual responses to light. In structure, melanopsin is an opsin, a retinylidene protein variety of...

 is most efficiently excited by light from the blue part of the spectrum (420–440 nm according to some researchers while others have reported 470–485 nm). These blue wavelengths are present in virtually all light sources, therefore their elimination requires special lights or filters which appear amber.

It is thought that the direction of the light may have an effect on entraining the circadian rhythm; light coming from above, resembling an image of a bright sky, has greater effect than light entering our eyes from below.

According to a 2010 study completed by the Lighting Research Center, daylight has a direct effect on circadian rhythms and, consequently, on performance and well-being. The research showed that students who experience disruption in lighting schemes in the morning consequently experience disruption in sleeping patterns. The change in sleeping patterns may lead to negatively impacted student performance and alertness. Removing circadian light in the morning delays the dim light melatonin onset by 6 minutes a day, for a total of 30 minutes for five days.

Enforced longer cycles

Studies by Nathaniel Kleitman
Nathaniel Kleitman
Nathaniel Kleitman was Professor Emeritus in Physiology at the University of Chicago. Author of the seminal 1939 book Sleep and Wakefulness, he is recognized as the father of American sleep research...

 in 1938 and by Derk-Jan Dijk and Charles Czeisler
Charles Czeisler
Charles A. Czeisler is a researcher and author in the field of circadian rhythms and sleep medicine. He holds both an M.D. and a Ph.D. and is currently the Chief and Director of the Division of Sleep Medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, MA, USA...

 in 1994/5 have put human subjects on enforced 28-hour sleep–wake cycles, in constant dim light and with other time cues suppressed, for over a month. Because normal people cannot entrain to a 28-hour day in dim light if at all, this is referred to as a forced desynchrony protocol. Sleep and wake episodes are uncoupled from the endogenous circadian period of about 24.18 hours and researchers are allowed to assess the effects of circadian phase on aspects of sleep and wakefulness including sleep latency and other functions.

Human health

Timing of medical treatment in coordination with the body clock may significantly increase efficacy and reduce drug toxicity or adverse reactions. For example, appropriately timed treatment with angiotensin converting enzyme inhibitors (ACEi) may reduce nocturnal blood pressure and also benefit left ventricular (reverse) remodelling.

A number of studies have concluded that a short period of sleep during the day, a power-nap, does not have any measurable effect on normal circadian rhythms, but can decrease stress and improve productivity.

There are many health problems associated with disturbances of the human circadian rhythm, such as seasonal affective disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...

 (SAD), delayed sleep phase syndrome
Delayed sleep phase syndrome
Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...

 (DSPS) and other circadian rhythm disorders. Circadian rhythms also play a part in the reticular activating system
Reticular activating system
The reticular activating system is an area of the brain responsible for regulating arousal and sleep-wake transitions.- History and Etymology :...

, which is crucial for maintaining a state of consciousness. In addition, a reversal in the sleep–wake cycle may be a sign or complication of uremia
Uremia
Uremia or uraemia is a term used to loosely describe the illness accompanying kidney failure , in particular the nitrogenous waste products associated with the failure of this organ....

, azotemia
Azotemia
Azotemia 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 compounds in the blood...

 or acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...

.

Studies have also shown that light has a direct effect on human health because of the way it influences the circadian rhythms.

Circadian rhythm and airline pilots

Due to the work nature of airline pilots, who often traverse multiple timezones 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 (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

. The NTSB cites this situation as a contributing factor to many accidents and has conducted multiple research studies in order to find methods of combating fatigue in pilots.

Disruption

Disruption to rhythms usually has a negative effect. Many travellers have experienced the condition known as jet lag
Jet lag
Jet lag, medically referred to as desynchronosis, is a physiological condition which results from alterations to the body's circadian rhythms; it is classified as one of the circadian rhythm sleep disorders...

, with its associated symptoms of fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

, disorientation and insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...

.

A number of other disorders, for example bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...

 and some sleep disorder
Sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning...

s, are associated with irregular or pathological functioning of circadian rhythms. Recent research suggests that circadian rhythm disturbances found in bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...

 are positively influenced by lithium
Lithium pharmacology
Lithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...

's effect on clock genes.

Disruption to rhythms in the longer term is believed to have significant adverse health consequences on peripheral organs outside the brain, particularly in the development or exacerbation of cardiovascular disease. The suppression of melatonin production associated with the disruption of the circadian rhythm may increase the risk of developing cancer.

Effect of drugs

Circadian rhythms and clock genes expressed in brain regions outside the suprachiasmatic nucleus
Suprachiasmatic nucleus
The suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...

 may significantly influence the effects produced by drugs such as cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

. Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.

See also

  • Actigraphy
    Actigraphy
    Actigraphy is a non-invasive method of monitoring human rest/activity cycles. A small actigraph unit, also called an actimetry sensor, is worn by a patient to measure gross motor activity. Motor activity often under test is that of the wrist, measured by an actigraph in a wrist-watch-like package....

     (also known as Actimetry)
  • ARNTL
    ARNTL
    Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene which is associated with susceptibility to hypertension and type 2 diabetes.-Function:...

  • ARNTL2
    ARNTL2
    Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Mop9, Bmal2, CLIF,, or ARNTL2, is a gene.Arntl2 is a mammalian paralog of the Drosophila Cycle gene. Homologs were isolated in fish, birds and mammals such as mice and humans...

  • Bacterial circadian rhythms
    Bacterial circadian rhythms
    Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three characteristics: in constant conditions Bacterial circadian rhythms, like other circadian rhythms, are endogenous "biological clocks" that have the following three...

  • Circaseptan
    Circaseptan
    A circaseptan rhythm is a cycle consisting of 7 days in which many biological processes of life resolve.-References:* Halberg F et al. 1965: "Spectral resolution of low-frequency, small-amplitude rhythms in excreted 17-ketosteroid: probable androgen-induced circaseptan desynchronization". Acta...

    , 7-day biological cycle
  • Circadian rhythm sleep disorders
  • Circadian oscillator
    Circadian oscillator
    Circadian oscillators are components of the biological clocks that regulate the activities of organisms in relation to environmental cycles and provide an internal temporal framework...

  • Cryptochrome
    Cryptochrome
    Cryptochromes are a class of blue light-sensitive flavoproteins found in plants and animals. Cryptochromes are involved in the circadian rhythms of plants and animals, and in the sensing of magnetic fields in a number of species...

  • CRY1 and CRY2: the cryptochrome family genes
  • Delayed sleep phase syndrome
    Delayed sleep phase syndrome
    Delayed sleep-phase syndrome , also known as delayed sleep-phase disorder or delayed sleep-phase type , is a circadian rhythm sleep disorder, a chronic disorder of the timing of sleep, peak period of alertness, the core body temperature rhythm, hormonal and other daily rhythms, compared to the...

  • Diurnal cycle
    Diurnal cycle
    A diurnal cycle is any pattern that recurs every 24 hours as a result of one full rotation of the Earth.In climatology, the diurnal cycle is one of the most basic forms of climate patterns. The most familiar such pattern is the diurnal temperature variation...

  • Light effects on circadian rhythm
    Light effects on circadian rhythm
    Numerous organisms maintain inherent individual daily rhythms to biological processes, known as circadian rhythms, that assist the organism in maintaining functional periodicity relative to the 24-hour day/night cycle of the earth...

  • Light in school buildings
    Light in school buildings
    Light in school buildings traditionally is from a combination of daylight and electric light to illuminate classrooms, hallways, cafeterias, offices and other interior areas. Light fixtures currently in use usually provide students and teachers with satisfactory visual performance, i.e., the...

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

    , PER2
    PER2
    Period circadian protein homolog 2 is a protein that in humans is encoded by the PER2 gene.PER2 contains glucocorticoid response elements and a GRE within the core clock gene Per2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo...

    , and PER3
    PER3
    Period circadian protein homolog 3 is a protein that in humans is encoded by the PER3 gene....

    : the period family genes
  • Photosensitive ganglion cell
    Photosensitive ganglion cell
    Photosensitive ganglion cells, also called photosensitive Retinal Ganglion Cells , intrinsically photosensitive Retinal Ganglion Cells or melanopsin-containing ganglion cells, are a type of neuron in the retina of the mammalian eye.They were discovered in the early 1990sand are, unlike other...

    : part of the eye which is involved in regulating circadian rhythm.

Further reading

  • Aschoff, J. (ed.) (1965) Circadian Clocks. North Holland Press, Amsterdam
  • Dunlap, J.C.; Loros, J.; DeCoursey, P.J. (2003) Chronobiology: Biological Timekeeping. Sinauer, Sunderland
  • Koukkari, W.L.; Sothern, R.B. (2006) Introducing Biological Rhythms. Springer, New York
  • Refinetti, R. (2006) Circadian Physiology, 2nd ed. CRC Press, Boca Raton


External links

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