Animal circadian rhythms

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, comes from the Latin circa, "around", and dies, "day", meaning literally "about a day." The formal study of biological temporal rhythms such as daily, 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 such as sunlight and temperature.

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


 * 1) 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 instance, you would not want the "wears sunglasses" behavior to be classified as a circadian rhythm - if there were no sunlight, the behavior would not persist.
 * 2) 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 and not by design.
 * 3) 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. Your wrist watch has no means of determining the local time - but your biological clock does.

Origin
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 the three mutations mapped to the same gene and was baptised 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 results in an interlocked feedback loop of gene products resulting in periodic fluctions 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". 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 talk to each other resulting in a synchronized and democratic 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 (such as those present in the liver). Thus, the information of the time of the day as determined by the eyes may travel to the clock in the brain and through that, clocks in the rest of the body may be synchronized. This is how many behavior such as drinking water, sleep/wake and body temperature are coordinately controlled by the biological clock.

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

Circadian rhythms also play a part in the reticular activating system in the reticular formation.

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 "free-running" rhythm. Each "day," their sleep cycle is pushed back or forward (depending on whether the endogenous period is longer or shorter than 24 hours). The environmental cues that each day reset the rhythms are called Zeitgebers (German, literally "Time Givers"). Interestingly, totally blind subterranean mammals (e.g., blind mole rat Spalax sp.) are able to maintain their endogenous clock in absence of the external stimuli.

Free running organisms still have a consolidated sleep-wake cycle when in an environment shielded from external cues, but the rhythm is not engrained and may become out of phase with other circadian, or ultradian rhythms such as temperature and digestion. 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.

Suprachiasmatic nucleus
The circadian "clock" in mammals is located in the suprachiasmatic nucleus (SCN), a distinct group 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.

Outside the SCN "master clock"
Recently, evidence has emerged that circadian rhythms are found in many cells in the body outside the SCN "master clock." Furthermore, liver cells, for example, appear to respond to feeding rather than to light. Cells from many parts of the body appear to have "free-running" rhythms.

Cells in the body that have their own rhythms are called peripheral oscillators. These tissues include the esophagus, lung, liver, 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.

Disruption
Disruption to rhythms usually has a negative effect in the short term. 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.

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

Relationship to cocaine
In addition, circadian rhythms and clock genes expressed in brain regions outside the SCN may significantly influence the effects produced by drugs such as cocaine.

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

Light and the biological clock
The ability of light to reset the biological clock depends on the phase response curve (to light). Depending on the phase of sleep, the light can advance or delay the circadian rhythm. The required illuminance varies from species to species, much lower light levels being 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).

References & Bibliography


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