Circadian rhythm

A circadian rhythm is an endogenously driven 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). The term circadian comes from the Latin circa, 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. Although circadian rhythms are endogenous ("built-in", self-sustained), they are adjusted (entrained) to the environment by external cues called zeitgebers, the primary one of which is daylight.

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 tree.

The first recorded observation of an endogenous circadian oscillation was by the French scientist Jean-Jacques d'Ortous de Mairan in 1729. He noted that 24-hour patterns in the movement of the leaves of the plant Mimosa pudica 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 and Seymour Benzer isolated the first clock mutant in Drosophila in the early seventies and mapped the "period" gene, the first discovered genetic component of a circadian clock. Joseph Takahashi discovered the first mammalian 'clock gene' (CLOCK) using mice in 1994.

The term "circadian" was coined by Franz Halberg 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. 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 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.
 * 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 radiation during the daytime. As a result, replication was relegated to the dark. The fungus Neurospora, which exists today, retains this clock-regulated mechanism.

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. 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" 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 eyes travels to the clock in the brain, and, through that, clocks in the rest of the body may be synchronised. This is how the timing of, for example, sleep/wake, body temperature, thirst, and appetite are coordinately controlled by the biological clock.

Importance in animals
Circadian rhythmicity is present in the sleeping and feeding patterns of animals, including human beings. There are also clear patterns of core body temperature, brain wave 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 ('daylength') is the most predictive environmental cue for the seasonal timing of physiology and behavior, most notably for timing of migration, hibernation and reproduction.

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 rhythm. Each "day", their sleep cycle is pushed back or forward, depending on whether their endogenous period is shorter or longer than 24 hours. The environmental cues that reset the rhythms each day are called zeitgebers (from the German, "time-givers"). It is interesting to note that 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.

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

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.

Arctic animals
Norwegian researchers at the University of 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.

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.

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 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 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 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.

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. 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).

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-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 secretion by the pineal gland
 * core body temperature
 * plasma level of cortisol.

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.

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 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 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, pancreas, spleen, thymus, 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 (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.

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 striking the retina.

In addition to light intensity, wavelength (or colour) of light is a factor in the entrainment of the body clock. Melanopsin 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 in 1938 and by Derk-Jan Dijk and Charles Czeisler 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 (SAD), delayed sleep phase syndrome (DSPS) and other circadian rhythm disorders. Circadian rhythms also play a part in the reticular activating system, 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, azotemia or acute renal failure.

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. 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, 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.

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 may significantly influence the effects produced by drugs such as cocaine. Moreover, genetic manipulations of clock genes profoundly affect cocaine's actions.