Circadian Rhythm – A Review

2010, Vol. 5 No. 2, Article 60

Dipak Banerjee*¹and Anjan Dandapat²

¹Ph.D. Scholar (Animal Physiology)
²Ph.D. Scholar (Animal Genetics and Breeding)
National Dairy Research Institute,
Karnal (Haryana), India-132001

*Corresponding Author; e-mail address: dipak_vet@yahoo.co.in

ABSTRACT

The physiological processes of organisms are regulated by a circadian rhythm. The circadian rhythm is regulated by the wavelength, intensity, timing and duration of the light stimulus. Biological rhythms affect the sleep–wake cycle, migration behaviour in birds, seasonal fattening, hibernation and reproductive cycles in animals. The circadian rhythm is ubiquitous in nature. Circadian rhythms appear to be generated at the cellular level. Daily biological rhythms are endogenously controlled by self-contained circadian clocks. The period length is controlled by a circadian oscillator (clock). The timing of sleep and wakefulness under natural conditions is in synchrony with the circadian control of the sleep cycle and all other circadian-controlled rhythms. Adverse effects may ensue when the sleep-wake cycle is out of phase with the rhythms that are controlled by the circadian clock. Circadian rhythm is related to the light/dark cycle of the solar day but it also persists in constant conditions. The environmental cues entraining the circadian rhythm are called Zeitgebers or circadian synchronizers. Temporal restrictions of feeding (RF) can phase-shift behavioural and physiological circadian rhythms in mammals. Phase advances of circadian rhythms happens for instance, in the liver, kidney, heart, pancreas and some brain structures, uncoupling them from the control of the SCN, whose entrainment to light remains intact.

KEY WORDS

Circadian rhythms, molecular basis, circadian clock, light, feeding.

INTRODUCTION

All the living organisms are exposed to the earth’s revolution around the sun with its cycle of day and night, of light and darkness and with the periodic changes in the length of the daily light and dark span along with the changes in seasons. Due to the rhythmicity of day and night most of the species exhibit daily changes in their behavior and/or physiology which generally arise from a timekeeping system within the organism. This timekeeping system is known as biological “clock” which allows the organisms to anticipate and prepare for the changes in the physical environment, thereby ensuring that the organism will “do the right thing” at the right time of the day. The biological clock provides internal temporal organization and ensures internal changes in coordination with one another (Vitaterna et al., 2001).
The physiological processes of organisms are regulated by a circadian rhythm. Circadian has been derived from Latin phrase “Circadiem” which means “about a day” (approximately 24 hours). French scientist Jean- Jacques d’Ortous de Marian first described this rhythm in the movement of plant leaves in the 1700s (Meijer and Rietveld, 1989). This finding suggested that the movements represented something more than a simple response to the sun and were controlled by an internal clock. The circadian rhythm is regulated by the wavelength, intensity, timing and duration of the light stimulus (Cardinali et al., 1972; Brainard et al., 1983, 1986; Takahashi et al., 1984). Graphical representation of biological rhythms is presented in Fig. 1.

BIOLOGICAL RHYTHMS

Biological rhythms affect the sleep–wake cycle, migration behaviour in birds, seasonal fattening, hibernation and reproductive cycles in animals. In the 1950's Colin Pittendrigh and Jürgen Aschoff carried out research work on circadian rhythmicity in fruit flies and humans, respectively. They are considered as founder of chronobilogy. The area of sleep research, which also is subsumed under the field of chronobiology, began to develop independently, with the identification of various sleep stages by Nathaniel Kleitman around the same time (Dement, 2000).
The periodic variation with shorter periods (higher requencies) than circadian is called ultradian rhythms. The circadian rhythms are super imposed upon rhythms with longer periods (or lower frequencies), the so called infradian rhythms, which include, among others, rhythms with a period of about 1 week (circaseptan rythms), rhythms with a period of about 30 days (circatrigintan rhythms) and rhythms with a period of about 1 year (circannual rhythms and/or seasonal variations) (Nicolau et al., 1983, Haus and Halberg, 1970). The different types of biological rhythms are presented in Table 1.

CHARACTERISTIC FEATURES OF CIRCADIAN RHYTHMS

According to De Mairan’s observations the circadian rhythm is self-sustained in nature. Thus, almost all diurnal rhythms that occur under natural conditions continue to cycle under laboratory conditions devoid of any external time giving cues from the physical environment. Circadian rhythms that are expressed in the absence of any 24-hour signals from the external environment are called free running. This indicates that the rhythm is not synchronized by any cyclic change in the physical environment. A diurnal rhythm should not be called circadian until it has been shown to persist under constant environmental conditions and thereby can be distinguished from those rhythms that are simply a response to 24-hour environmental changes. However, almost all diurnal rhythms are found to be circadian.
Uncontrolled geomagnetic cues play a role in the persistence of rhythmicity can be refuted by a second characteristic feature of circadian rhythms. These cycles persist with a period of close to 24 hours. If the rhythms were exogenously driven, they should persist with a period of exactly 24 hours. However, the seeming imprecision is considered as an important feature of rhythmicity. The deviation from a 24-hour cycle actually provides means for the internal timekeeping system to be continuously aligned by and aligned to the light-dark environment (Pittendrigh, 1960). This continuous adjustment results in greater precision in controlling the timing, or phase, of the expressed rhythms, because little drift is allowed to occur before the rhythm is “reset” to the correct phase.
In the absence of a dark-light cycle or other exogenous time signal (i.e., a Zeitgeber) the persistence of rhythms clearly seems to indicate the existence of some kind of internal timekeeping mechanism, or biological clock. The persistence of rhythmicity does not necessarily exclude the possibility that other, uncontrolled cycles generated by the Earth’s revolution on its axis might be driving the rhythm (Aschoff, 1960).
A third characteristic feature of circadian rhythms is their ability to be synchronized, or entrained, by external time cues, such as the light-dark cycle. Circadian rhythms can persist in the absence of external time cues (meaning that they are not driven by the environment), normally such cues are present and the rhythms are aligned to them. Accordingly, if a shift in external cues occur (e.g., following travel across time zones), the rhythms will be aligned to the new cues. This alignment is known as entrainment.
Initially, it was not clear whether entrainment was achieved by modulating the rate of cycling (i.e., whether the cycle was shortened or lengthened until it was aligned to the new cues and then reverted to its original length) or whether entrainment was achieved by discrete “resetting” events. Experiments resulting from this controversy led to fundamental discoveries. The organism’s response to light (i.e., whether a cycle advances, is delayed, or remains unchanged) differs depending on the phase in the cycle at which it is presented (Pittendrigh, 1960). Thus, exposure to light during the early part of the individual’s “normal” dark period generally results in a phase delay, whereas exposure to light during the late part of the individual’s normal dark period generally results in a phase advance. This difference in responses can be represented by a phase-response curve (Fig. 2). This curve can show the manner in which an organism will entrain not only to shifts in the light-dark cycles but also to unusual light cycles, such as non-24-hour cycles or different light: dark ratios. The existence of a phase-response curve also predicts that entrainment is achieved by discrete resetting events rather than changes in the rate of cycling. The effects of a rhythm-resetting signal, such as exposure to light by animals other-wise kept in continuous darkness, can shift the rhythm either back (upper panel) or ahead (lower panel), depending on when during the cycle the signal is presented in Fig. 3.
Changes in circadian rhythm in response to changes in light exposure are shown in Fig. 4. In addition to the duration of the light exposure, the light intensity can also affect cycling periods when organisms are left in constant source of light. Thus, the effect of exposure to brighter light intensities varies from species to species. In some species it can lengthen and in other species it can shorten this period. This phenomenon has been dubbed “Aschoff’s rule” (Aschoff, 1960).
However, the light-dark cycle clearly is the major Zeitgeber for all organisms, other factors such as social interactions, activity or exercise, and even temperature also can modulate a cycle’s phase. Temperature can affect the phase of a cycle without substantially altering the rate of cycling. This indicates that the cycle may start at an earlier or later than normal time but still have the same length.
The circadian rhythm is ubiquity in nature. It exists in a broad array of biological processes and organisms, with similar properties and even similar phase-response curves to light.
Circadian rhythms appear to be generated at the cellular level. The rhythms of unicellular organisms (e.g., algae or the dinoflagellate Gonyaulax) are much the same as rhythms of highly complex animals. The expression of genes and the production of protein encoded by genes are required for normal clock function.

MOLECULAR BASIS OF CIRCADIAN RHYTHMS

Random mutation was carried out into the DNAs of the fruit fly, Drosophila melanogaster, and of the filamentous fungus Neurospora by using several mutagens. Then the resulting mutant organisms were screened for rhythm abnormalities. This mutagenesis approach led to the discovery of the first circadian clock mutants, which were called period (per) and frequency (frq, pronounced “freak”). The genes that carried the mutations in these organisms were cloned in the 1980s (Wager-Smith and Kay, 2000). However, researchers sought to isolate the equivalent genes in mammals (i.e., mammalian homologs'). Finally, in 1994, researchers began a similar mutagenesis screening approach in the mouse and described the first mouse circadian mutation, called Clock (King and Takahashi, 2000). In 1997 the gene affected by this mutation became the first mammalian circadian clock gene to be cloned (King and Takahashi, 2000). Recent advances in molecular biology and genetics led to the cloning of many mammalian ‘‘clock’’ genes and to the discovery of new, extracerebral sites containing circadian oscillators (Yamazaki et al., 2000). Hierarchical architecture of circadian rhythm from gene, to cell, to nerve nuclei, to brain, and to system is depicted in Fig. 5.

CIRCADIAN CLOCK

Daily biological rhythms are endogenously controlled by self-contained circadian clocks. The suprachiasmatic nuclei of the hypothalamus (SCN) are believed to be the anatomical locus of the circadian pacemaker (Silver and Moore, 1998). The period length is controlled by a circadian oscillator (clock) (Ikonomov et al., 1998). The biological timer can act as an alarm clock to initiate a physiological process of an organism at an appropriate phase of the daily environmental cycle. It can also help an organism prepare in anticipation of actual need. Another important function in some organisms is the accurate measurement of ongoing time throughout the daily cycle. The circadian clock can act like an instrument for estimating the day length or night length: thus, seasonal phenomena which respond to changing of day length can be regulated appropriately (Dunlap et al., 2004). This circadian oscillator, entrained by the light-day cycle via the retinohypothalamic tract, can impose circadian patterns on a wide array of physiological and behavioural processes (Cassone and Stephan, 2002). Physiological functions under the control of biological clock are given in Table 2.

ANATOMICAL ORGANIZATION OF THE CIRCADIAN CLOCK

Studies of unicellular organisms depict the cellular nature of the system generating circadian rhythms. In higher organisms the circadian pacemaker is located in cells of specific structures of the organism. These structures are present in certain regions of the brain (i.e., the optic and cerebral lobes) in insects; the eyes in certain invertebrates and vertebrates; and the pineal gland in non mammalian vertebrates. In mammals, the circadian clock resides in two clusters of nerve cells called the suprachiasmatic nuclei (SCN), which are located at the anterior hypothalamus. The landmark discovery in the early 1970s demonstrated that the SCN is the site of primary regulation of circadian rhythmicity in mammals gave researchers a focal point for their research. By damaging (i.e., lesioning) the SCN in rats, researchers could disrupt and abolish endocrine and behavioral circadian rhythms (Klein et al., 1991). Furthermore, by transplanting the SCN from other animals into the animals with the lesioned SCN, researcher could restore some of the circadian rhythms. Finally, the SCN’s role as a master pacemaker regulating other rhythmic systems was revealed by similar studies in hamsters, which demonstrated that the restored rhythms exhibited the clock properties (i.e., the period, or phase, of the rhythm) of the donor rather than of the host (Ralph et al., 1990).
Circadian rhythms could persist in isolated lungs, livers, and other tissues grown in a culture dish (i.e., in vitro) that were not under the control of the SCN (Yamazaki et al., 2000). These findings indicate that most of cells and tissues of the body can modulate their activity on a circadian basis. However, such observations do not suppress the central role played by the SCN as the master circadian pacemaker. SCN somehow regulates the entire 24 hour temporal organization of cells, tissues, and the whole organism through neural or neurohormonal signal. However, the characteristics of the circadian signal in which the SCN “talks” to the rest of the body remain unknown (Stokkan et al., 2001).

EFFECT OF SCN ON SLEEP-WAKE CYCLE

Although the effects of SCN lesions on numerous rhythms have been elucidated, their effects on sleep are less clear. Thus, SCN lesions clearly disrupt the consolidation and pattern of sleep in rats but have only minimal effects on the animals’ amount of sleep or sleep need (Mistlberger et al., 1987). Sleep is subject to two essentially independent control mechanisms:
(1) the circadian clock that modulates the propensity for sleep and
(2) a homeostatic control that reflects the duration of prior waking (i.e., “sleep debt”).
Recent studies suggest that SCN lesions can affect the amount of sleep in squirrel and monkeys. Moreover, sleep studies in mice carrying changes (i.e., mutations) in two of the genes influencing circadian cycles (i.e., the DBP and Clock genes) indicated that these mutations resulted in changes in sleep regulation (Franken et al., 2000). These observations raise the intriguing possibility that the homeostatic and circadian controls may be more interrelated with each other.

IMPORTANCE OF THE CIRCADIAN CLOCK

Nearly all physiological and behavioral functions in animals occur on a rhythmic basis, which in turn leads to dramatic diurnal rhythms in animal performance capabilities. A disturbed circadian rhythmicity in animals has been associated with a variety of mental and physical disorders and may negatively impact safety, performance, and productivity. Adverse effects of disrupted circadian rhythmicity may be linked to disturbances in the sleep-wake cycle. Some rhythmic processes are more affected by the circadian clock than by the sleep-wake state, whereas other rhythms are more dependent on the sleep-wake state.
The timing of sleep and wakefulness under natural conditions is in synchrony with the circadian control of the sleep cycle and all other circadian-controlled rhythms. Adverse effects may ensue when the sleep-wake cycle is out of phase with the rhythms that are controlled by the circadian clock.
Circadian rhythm abnormalities also are often associated with various disease states, but the importance of these rhythm abnormalities in the development of the disease remains unknown. If scientists knew more about the mechanisms responsible for the rhythmicity of these disorders, they might be able to identify more rational therapeutic strategies to influence these events. Dramatic changes occur in the circadian clock system with advanced age; these changes may underlie, or at least exacerbate, the age-related deterioration in the physical and mental capabilities of aged ones.

CIRCADIAN RHYTHMS REGULATION BY LIGHT

Several experimental results show that light is the most important synchronizer of circadian rhythms. Light sets and resets the timing of the circadian timekeeping system, to ensure its proper functioning. Light exposure early in the morning resets the circadian system to adjust for its propensity to phase-delay, and light exposure in the evening is necessary to adjust for phase-advances in the master clock (Czeisler et al., 1990, Lewy et al., 1987).
Circadian rhythm is related to the light/dark cycle of the solar day but it also persists in constant conditions (e.g. constant light). The rhythm period can be reset by exposure to a light or dark pulse. It has been seen that if there is a change in the lighting conditions, the animal can gradually adjust to the new pattern provided and it does not deviate too much from the species norm. If animals are kept in total darkness for a long period of time they start to display a “free-running” rhythm (Redman et al., 1983; Thomas and Armstrong, 1988). In diurnal animals the sleep cycle moves forward approximately one hour a day; their free-running rhythms are about 25 hours but in nocturnal animals the free-running rhythm is about 23 hours. Even in total darkness, unless the environment is shielded from all external cues, the free-running rhythm is influenced by events occurring regularly on a daily basis. Continuous light treatment results in suppression of circadian rhythmicity of locomotor activity (Homna and Hiroshige, 1978; Chesworth et al., 1987) in rats. Several other circadian rhythms are seen in rats like behavioural, temperature and some humoral rhythms depending on the intensity of light (Homna and Hiroshige, 1978; Eastman and Rechtschaffen, 1983; Deprés-Brummer et al., 1995). The environmental cues, entrain the circadian rhythm, are called Zeitgebers or circadian synchronizers. Many environmental and behavioural stimuli act as circadian synchronizers, like water and food intake, motor activity, sleep-wake rhythm, corticosterone release, activity of pineal N-acetyltranferase enzyme and body temperature (Rusak and Zucker, 1979). The most important synchronizing trigger of circadian rhythmicity is environmental light/dark (LD) cyclicity. In the absence of external cues, the rhythm may become out of phase with, for instance, the ultradian rhythm of digestion. Biological functions, such as hormone production, cell regeneration and brain activation as measured by an electroencephalogram (EEG), and overall behavioural patterns (sleeping, eating) are linked to the circadian cycle.
Information about day length travels from the SCN to the pineal gland. The pineal gland secretes the hormone melatonin. The secretion reaches its peak at night and wanes during the day (Zucker et al., 1983). Some recent findings suggest that the SCN can also spread its message directly to peripheral organs and tissues through the autonomic nervous system (Bartness et al., 2001; la Fleur, 2003; Buijs et al., 2006).
If entraining effects of the light-dark cycle is absent then the circadian system free-runs. Time-isolation studies suggest that the circadian system can gradually shift. It is also seen that it may even become completely desynchronized with respect to external environmental cycles (Czeisler et al., 1980). Thus, failure to achieve such necessary adjustments in the timing of the circadian system, either because of deprivation of light cues, knowledge of time, or societal pressures (Elmore et al., 1992, Mistlberger and Skene, 2005), could lead to circadian misalignment or result in circadian disorders. Paradoxically, the ability of organisms to free-run is considered an advantage, as it allows them to maintain a stable phase relation with the environmental cycles and/or to adapt to seasonal variations in day length (Paranjpe and Sharma, 2005).

CIRCADIAN RHYTHMS REGULATION BY FEEDING

Feeding-entrained circadian system seems to be independent of the light-dark fluctuations of the solar day in different animals (Mistlberger, 1994; Stephan, 2002). Temporal restrictions of feeding (RF) can phase-shift behavioural and physiological circadian rhythms in mammals. It is postulated that changes in biological rhythms are caused by a food-entrainable oscillator (FEO), independent of the SCN (Mieda et al., 2006). In restricted feeding condition a (single period) scheduled at a fixed time of the day, mice (Mus musculus) adapt to this condition within a few days by feeding during the period of food availability and increasing food-seeking activity in the preceding hours (food anticipatory activity, FAA) (Hastings et al., 2003; Lowrey and Takahashi, 2004). Phase advances of circadian rhythms happens, for instance, in the liver, kidney, heart, pancreas and some brain structures, uncoupling them from the control of the SCN, whose entrainment to light remains intact (Damiola et al., 2000; Hara et al., 2001; Stokkan et al., 2001; Wakamatsu et al., 2001; Mendoza, 2006). It is postulated that feeding fasting signals may be involved in the entrainment of the peripheral circadian oscillators (Damiola et al., 2000; Stokkan et al., 2001). Existence of the FEO has not been unequivocally established. Some studies suggest that the dorsomedial hypothalamic nucleus (DMH) is a key structure for FEO expression (Gooley et al., 2006, Mieda et al., 2006). The results of few studies in rats with electrolytic DMH lesions do not, however, support this hypothesis. The circadian mechanism of FEO at the molecular level is not clear (Mendoza, 2006). The evidence supporting the existence of this feeding-entrained circadian system has been obtained only during restriction of feeding (RF); it is likely that if such a system exists it would also participate in the regulation of body rhythms in everyday conditions.

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