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Circadian rhythm

A circadian rhythm is a roughly-24-hour cycle in the physiological processes of living beings, including plants, animals, fungi and cyanobacteria. The term "circadian", coined by Franz Halberg,^[1] comes from the Latin circa, "around", and diem or dies, "day", meaning literally "about a day." The formal study of biological temporal rhythms such as daily, tidal, weekly, seasonal, and annual rhythms, is called chronobiology.

In a strict sense, circadian rhythms are endogenously generated, although they can be modulated by external cues, primarily daylight.

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1 History
2 Criteria
3 Origin
4 Importance in animals
- 4.1 Impact of light-dark cycle
- 4.2 Arctic animals
5 The biological clock
- 5.1 Determining one's circadian rhythm
- 5.2 Outside the "master clock"
6 Light and the biological clock
7 Human health
- 7.1 Disruption
- 7.2 Relationship to cocaine
8 See also
9 Notes
10 Further reading

History

The first endogenous circadian oscillation was observed in the 1700s by the French scientist Jean-Jacques d'Ortous de Mairan who noticed that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica continued even when the plants were isolated from external stimuli.

The earliest known account of a circadian rhythm dates from the fourth century BC, when Androsthenes, in descriptions of the marches of Alexander the Great, described diurnal leaf movements of the tamarind tree.

Criteria

General criteria of circadian rhythms

The rhythm persists in constant conditions (for example, constant dark) with a period of about 24 hours. The rationale for this criterion is to distinguish circadian rhythms from those "apparent" rhythms that merely respond to external periodic cues. For example, the behavior of wearing sunglasses would not be classified as a circadian rhythm - if there were no sunlight, the behavior would not persist.
The rhythm has the same period over a range of temperatures (i.e., it is temperature-compensated). The rationale for this criterion is to distinguish circadian rhythms from other biological rhythms arising due to circular nature of a reaction pathway - for instance, Kreb's cycle in metabolism. At a low enough or high enough temperature, the period of the circular reaction may reach 24 hours, but it would be merely coincidental.
The rhythm can be reset by exposure to an external stimulus. 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 zones illustrates the necessity of the ability to adjust the biological clock so that it can determine the local time and anticipate what will happen next.

Origin

This section does not cite any references or sources.
Please improve this section by adding citations to reliable sources. Unverifiable material may be challenged and removed. (October 2007)

Photosensitive proteins and circadian rhythms are believed to have originated in the earliest cells, with the purpose of protecting replicating DNA from high ultraviolet radiation during the daytime. As a result, replication was relegated to the dark. The fungus Neurospora, which exists today, retains this clock-regulated mechanism.

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. Previous explanations of the prokaryotic circadian timekeeper were dependent upon a DNA transcription / translation feedback mechanism, and, although this has not been shown to be the case, it is still believed to hold true for eukaryotic organisms. Indeed, although the circadian systems of eukaryotes and prokaryotes have the same basic architecture: input - central oscillator - output, they do not share any homology. This implies probable independent origins.

In 1971, Konopka and Benzer first identified a genetic component of the biological clock using the fruit fly as a model system. Three mutant lines of flies displayed aberrant behavior - one had a shorter period, another had a longer one and the third had none. All of the three mutations mapped to the same gene, which was named period. The same gene was identified to be defective in a sleep disorder called FASPS (Familial Advanced Sleep Phase Syndrome) in human beings thirty years later - underscoring the conserved nature of the molecular circadian clock through evolution. We now know many more genetic components of the biological clock. 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.

Our understanding of the biological clock has come a long way from Imagine It To Be A Sine Wave Generator^{[citation needed]}. We now know 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 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 sychronize 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.

Importance in animals

Circadian rhythms are important in determining the sleeping and feeding patterns of all animals, including human beings. There are clear patterns of core body temperature, brain wave activity, hormone production, cell regeneration and other biological activities linked to this daily cycle. 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 daylength.

«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 ('daylength') is the most predictive environmental cue for the seasonal timing of physiology and behavior, most notably for timing of migration, hibernation and reproduction.»^[2]

Impact of light-dark cycle

The rhythm is linked to the light-dark cycle. Animals kept in total darkness for extended periods eventually function with a freerunning rhythm. Each "day," their sleep cycle is pushed back or forward, depending on whether the endogenous period is shorter or longer than 24 hours. The environmental cues that each day reset the rhythms are called Zeitgebers (from the German, Time Givers).^[3] It is interesting to note that totally-blind subterranean mammals (e.g., blind mole rat Spalax sp.) are able to maintain their endogenous clock in absence of the external stimuli. Freerunning organisms that normally have one consolidated sleep episode will still have it 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.

Some say that sleep/wake may, in these circumstances, become out of phase with other circadian or ultradian rhythms such as temperature and digestion.^{[citation needed]} This 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.

Arctic animals

Norwegian researchers at the University in Tromsø have shown that some arctic animals (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 at 78 degrees North 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.^[4]^[5]

However, another study in northern Alaska found that ground squirrels and porcupines 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.^[6]

The biological clock

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 eyes contains not only "classical" photoreceptors but also photoresponsive retinal ganglion cells. These cells, which contain a photo pigment called melanopsin, 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.

It appears that the SCN takes the information on day length from the retina, interprets it, and passes it on to the pineal gland (a pea-like structure found on the epithalamus), which then secretes the hormone melatonin in response. Secretion of melatonin peaks at night and ebbs during the day.

Human's circadian rhythms 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).^[7]

Determining one's circadian rhythm

The classic phase markers for measuring the timing of a mammal's circadian rhythm are melatonin secretion by the pineal gland and body temperature.

For temperature studies, people must remain awake but calm and semi-reclined in near darkness while their rectal temperatures are taken continuously. The average human adult's temperature reaches its minimum at about 05:00 (5 a.m.), about two hours before habitual wake time, though variation is great among normal chronotypes.

Melatonin is absent from the system or immeasurably low during the day. 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. 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 most 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 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.^[8]

One method used for measuring melatonin offset is to analyze repeated urine samples throughout the morning and day for the presence of the melatonin metabolite 6-sulphatoxymelatonin (aMT6s). Laberge et al in Quebec in 1997 used this method in a study which confirmed the frequently found delayed circadian phase in healthy adolescents.^[9]

Outside the "master clock"

More-or-less independent circadian rhythms are found in many organs and cells in the body outside the SCN "master clock." These clocks, called peripheral oscillators, are found in esophagus, lung, liver, pancreas, spleen and thymus. There is some evidence the olfactory bulb and prostate may also experience oscillations when cultured, suggesting 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 (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; much lower light levels are required to reset the clocks in nocturnal rodents than in humans.

In addition to light intensity, wavelength (or color) of light is an important factor in the degree to which the clock is reset. Melanopsin is most efficiently excited by blue light (420-440 nm).^[10]

By depriving people of daylight and other external time cues, scientists have learned that most people's biological clocks work on a 25-hour cycle when subjects are allowed to use electric light at will. But because daylight or other lighting can reset circadian rhythms, our biological cycles normally follow the 24-hour cycle of the earth's rotation, rather than our innate cycle which averages 24 hours and 11 minutes for adults.^[11] Circadian rhythms can be minimally affected by almost any kind of external time cue, such as the beeping of an alarm clock, the clatter of a garbage truck, or the timing of meals.

Human health

There are many health problems associated with a disturbance in the human circadian rhythm, such as Seasonal Affective Disorder (SAD), and delayed sleep phase syndrome (DSPS).^[12] Circadian rhythms also play a part in the reticular activating system which is crucial for maintaining a state of consciousness.

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.

A number of other disorders, for example bipolar disorder and some sleep disorders are associated with irregular or pathological functioning of circadian rhythms. Recent research suggests that circadian rhythm disturbances found in bipolar disorder are positively influenced by lithium's effect on clock genes.^[13]

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. 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) remodeling.

Shift work, particularly the night shift, has in December 2007 been listed by the World Health Organization (WHO) as a "probable cause" of cancer.^[14]

Relationship to cocaine

Circadian rhythms and clock genes expressed in brain regions outside the SCN may significantly influence the effects produced by drugs such as cocaine.^[15]^[16] Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.^[17]

Notes

^ http://www.msi.umn.edu/~halberg Halberg Chronobiology Center
^ Zivkovic, Bora "Coturnix" (August 13, 2005 / July 25, 2007). Clock Tutorial #16: Photoperiodism - Models and Experimental Approaches. A Blog Around the Clock. ScienceBlogs. Retrieved on 2007-12-09.
^ Circadian rhythms. Rapid eye movement (REM) sleep. Armenian Medical Network (2007). Retrieved on 2007-09-19.
^ Spilde, Ingrid. "Reinsdyr uten døgnrytme", forskning.no, December 2005. Retrieved on 2007-11-24. (Language: Norwegian, Bokmål)
^ Zivkovic, Bora, aka Coturnix, chronobiologist. Circadian Rhythms, or Not, in Arctic Reindeer. A Blog around the Clock. ScienceBlogs.com. Retrieved on 2007-11-24.
^ Zivkovic, Bora, aka Coturnix, chronobiologist (February 11, 2007). Small Arctic Mammals Entrain to Something during the Long Summer Day. A Blog Around the Clock. ScienceBlogs.com. Retrieved on 2007-11-26.
^ Scheer, Frank A. J. L.; Kenneth P. Wright, Jr., Richard E. Kronauer, Charles A. Czeisler (2007-08-08). "Plasticity of the Intrinsic Period of the Human Circadian Timing System". PLos ONE. Retrieved on 2007-12-31.
^ Benloucif, S.; Guico, M.J.; Reid, K.J.; Wolfe, L.F.; L'Hermite-Baleriaux, M.; Zee, P.C. (2005). "Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans.". J Biol Rhythms 20 (2): pages 178-88. Chicago, Illinois, USA: Center for Sleep and Circadian Biology, Departments of Neurology, Northwestern University Feinberg School of Medicine. Retrieved on 2007-12-18.
^ Laberge, L.; Lesperance, P.; Tremblay, R.; Lambert, C.; Montplaisir, J. (1997). "Phase delay of 6-sulphatoxymelatonin in normal adolescents" (in English). Sleep Research 26: p. 727. Québec, Canada: Centre d'etude du Sommeil, Hopital du Sacre-Coeur, Département de Psychologie, Département de Pharmacologie, Departement de Psychiatrie, Université de Montréal. Retrieved on 2007-12-18.
^ Newman LA, Walker MT, Brown RL, Cronin TW, Robinson PR: "Melanopsin forms a functional short-wavelength photopigment", Biochemistry. 2003 Nov 11;42(44):12734-8.
^ Human Biological Clock Set Back an Hour (1999). Retrieved on 2007-09-23.
^ Circadian Rhythms and Sleep. Circadian Rhythms and Sleep. Serendip (2007). Retrieved on 2007-09-19.
^ http://www.nimh.nih.gov/press/lithiumenzyme.cfm
^ IARC: Press Release Nr. 180 «Shiftwork that involves circadian disruption is “probably carcinogenic to humans”.»
^ Uz T, Akhisaroglu M, Ahmed R, Manev H (2003). "The pineal gland is critical for circadian Period1 expression in the striatum and for circadian cocaine sensitization in mice". Neuropsychopharmacology 28 (12): 2117-23. PMID 12865893.
^ Kurtuncu M, Arslan A, Akhisaroglu M, Manev H, Uz T (2004). "Involvement of the pineal gland in diurnal cocaine reward in mice". Eur J Pharmacol 489 (3): 203-5. PMID 15087244.
^ McClung C, Sidiropoulou K, Vitaterna M, Takahashi J, White F, Cooper D, Nestler E (2005). "Regulation of dopaminergic transmission and cocaine reward by the Clock gene". Proc Natl Acad Sci U S A 102 (26): 9377-81. PMID 15967985.