1. The Earth's rotation around its axis generates daily en- vironmental cycles. The most conspicuous daily environmental cycles are those of ambient temperature and illumination. The daily environmental cycle of greatest importance to organisms is the alternation of light and darkness. A civil day lasts 24.0 hours and includes a seasonally-variable interval of light (day), a variable interval of darkness (night), and two twilights (dawn and dusk). Many human populational activities exhibit daily rhythmicity in synchrony with the civil day.

2. Biological processes that cycle in 24-hour intervals are called daily rhythms (or, less often, nycthemeral rhythms). When a daily rhythm is endogenously generated, but still susceptible to modulation by 24-hour environmental cycles, it is called a circadian rhythm. Many behavioral processes of individual organisms exhibit daily and/or circadian rhythmicity, including locomotor activity, feeding, excretion, sensory processing, and learning capability. Rhythms of locomotor activity have been the most thoroughly-studied behavioral rhythms.

3. Many autonomic processes of individual organisms exhibit daily and/or circadian rhythmicity, including the control of body temperature, cardiovascular function, melatonin secretion, cortisol secretion, metabolism, and sleep. Rhythms of body temperature have been the most thoroughly-studied autonomic rhythms. The body temperature rhythm of a representative tree shrew (a small, primitive primate) is depicted in Figure 1. Specific information about rhythmicity in human vital signs is available here.

4. Under constant environmental conditions, circadian rhythms freerun with periods (durations) slightly different from 24.0 hours. However, in some species rhythmicity may be inhibited by constant light and, in other species, by constant darkness. In those species that exhibit free-running rhythms in constant light, the period of the rhythm is affected by the intensity of the light (Aschoff's rule). Some drugs, such as methamphetamine and deuterium oxide, can also affect circadian period.

5. Although circadian period can be transiently affected by environmental factors, the base-value of period is genetically determined. Different species tend to have different circadian periods, and single-gene mutations that affect circadian period have been described in various species. Four well-known genes that affect circadian period are per in fruit flies, frq in bread mold, tau in golden hamsters, and clock in domestic mice.

6. The master circadian pacemaker in mammals is located in the suprachiasmatic nucleus in the rostroventral hypotha- lamus (Figure 2). Lesion studies identified it in 1972, and in vitro and in vivo functional studies, as well as transplant studies, have repeatedly corroborated the finding since then.

7. The suprachiasmatic nucleus (SCN) has two main subdivisions: the ventrolateral (or core) region and the dorso- medial (or shell) region. Neurons in the ventrolateral region are generally not intrinsically rhythmic and use GABA (gamma aminobutiric acid) and VIP (vasoactive intestinal polypeptide) as their main neurotransmitters, whereas cells in the dorsomedial region are intrinsically rhythmic and use GABA and AVP (arginine vasopressin) as their main neurotransmitters. The ventrolateral region, which receives most sensory input, projects heavily to the dorsomedial region.

8. Great progress has been made in the study of molecular mechanisms of circadian rhythmicity during the last decade. The circadian clock is made up of transcriptional-translational loops that, in most animals, involve the per, clk, and cyc (or bmal1) genes (Figure 3). In mammals, CLK and BMAL1 are transcription factors that regulate the expression of per and cry, whose products (PER and CRY) inhibit CLK and BMAL1 in a negative feedback loop.

9. The pineal gland, the eyes, and other organs exhibit intrinsic circadian rhythmicity, at least in some vertebrate species. These multiple pacemakers seem to be under the control of the master circadian pacemaker located in the suprachiasmatic nucleus.

10. According to the non-parametric theory of entrainment, entrainment (synchronization) of circadian rhythms is attained by discrete daily phase-shifts of the circadian pacemaker that amount to the difference between the period of the pacemaker and the period of the zeitgeber (synchronizer): . Every species has a limited range of entrainment, but this range may be expanded if the zeitgeber frequency is a multiple or submultiple of the circadian frequency.

11. Although entrainment is established by a non-parametric mechanism, it is modulated by various parametric me- chanisms. Some important parametric effects of light on circadian rhythms are those associated with masking, after-effects, and dark adaptation. One of the parametric effects of light -- namely, masking -- may rival entrainment in the control of the temporal organization of behavioral and autonomic functions in natural environments.

12. The eye is the only photosensitive organ in mammals. In other vertebrates, photic information can also be acquired by the pineal gland, by the parietal eye (or the parapineal organ), and by additional deep brain photoreceptors. Three types of photoreceptors in the eye provide redundant input to the circadian system: rods, cones, and photosensitive ganglion cells (Figure 4). Melanopsin seems to be the photopigment used by photosensitive ganglion cells.

13. Three main neural pathways provide afference to the suprachiasmatic nucleus (SCN). The retino-hypothalamic tract connects retinal ganglion cells to the SCN via a mono-synaptic pathway that uses glutamate as its main neurotransmitter. The geniculo-hypothalamic tract connects the intergeniculate islet of the thalamus to the SCN via a mono-synaptic pathway that uses neuropeptide Y as its main neurotransmitter. The raphe- hypothalamic pathway connects raphe nuclei to the SCN and uses serotonin as its neurotransmitter. The retino-hypothalamic tract is the main carrier of photic information, whereas the two other pathways carry non-photic information.

14. Although light is the zeitgeber that has been most thoroughly studied, several non-photic environmental stimuli have been shown to also entrain circadian rhythms. They include ambient temperature, food availability, physical activity (exercise), and social contact. Non-photic stimuli seem not to have as strong an influence on the circadian system as light has. However, it is well established that information about food availability can act directly on a slave pacemaker (the food-entrainable oscillator), as well as on the master pacemaker, to entrain circadian rhythms.

15. Very little is known about how the circadian pacemaker acquires the information about temperature and nutritional state that is needed for non-photic entrainment. Temperature signals are available from cold- and warm-sensitive cells on the skin and in the body core. Hunger and satiety signals are available from the blood concentration of nutrients, taste and smell of the food being ingested, gastric distension, gastric contents, and blood levels of various hormones secreted by the stomach, by the intestines, and by fat cells.

16. Circadian rhythmicity is exhibited by many variables simultaneously, and different variables reach their daily peaks at different times of the day (Figure 5). Although the circadian pacemaker does not generate each and every rhythm individually, the causal connections between different rhythms are not fully known. It is known that the rhythm of body temperature is not caused either by the rhythm of activity or by the rhythm of feeding. Body temperature is under both homeostatic control and circadian control. The two mechanisms act independently on effector organs responsible for the regulation of body temperature. The circadian system generates the circadian rhythmicity of body temperature. The thermo- regulatory system restricts this rhythmicity according to its set point and its range of hysteresis error. Likewise, sleep and feeding are homeostatic processes gated by the circadian system.

17. Circadian rhythmicity is an evolutionarily old process that is found in all domains of life today. Some organisms are diurnal, some are nocturnal, and some are crepuscular. The circadian systems of diurnal and nocturnal organisms do not seem to differ, and the adoption of diurnal or nocturnal niches is believed to be determined by mechanisms located downstream from the pacemaker.

18. The SCN efference (output) relies on neural connections (primarily to other hypothalamic sites) as well as on an as-yet unidentified diffusible substance. The hypothalamic paraven- tricular nucleus (PVN) is a main target of the SCN efference associated with circadian rhythmicity of the autonomic nervous system. The dorsomedial hypothalamic nucleus (DMH) seems to be a major target for efference associated with behavioral and endocrine rhythms. Many of the SCN projections identified in anatomical studies have not yet been investigated in functional studies.

19. In many organisms, circadian rhythmicity is not present at birth. It develops during early life and often degenerates in old age. During adulthood, circadian rhythms can be modulated by infradian rhythms such as the reproductive cycle and annual rhythms. The circadian systems of males and females do not differ to a great extent.