Circadian physiology

Abstract

Circadian physiology refers to biological processes that are rhythmic with the time scale of a day. Parameters of circadian rhythmicity are mean level, phase, period, amplitude, waveform, and robustness. Circadian physiology is an overall feature of life and is well conserved during evolution from unicellular to multicellular organisms. Circadian physiology is governed by a circadian system that is capable to generate - without any environmental cue - self-sustained free-running or endogenous rhythms. These endogenous rhythms have a period length of approximately, but not precisely, 24 h; they are thus called circadian rhythms. The circadian system influences a variety of behavioral and autonomic functions. In normal life, circadian rhythms are entrained to (synchronized with) environmental cycles. Environmental cues that are able to synchronize circadian rhythms are called zeitgebers. For all living organisms, the change between day and night is the most important zeitgeber. In multicellular organisms, the circadian system has a hierarchical architecture and comprises a central circadian rhythm generator (a master clock) as well as multiple subsidiary clocks in the periphery (slave oscillators or peripheral clocks). Both the central circadian rhythm generator and the slave oscillators contain a molecular clockwork comprising clock genes and their protein products that interact with each other in transcriptional/translational feedback loops and control the expression of clock-controlled genes. However, there is an important difference between the central circadian rhythm generator, the master clock, and the slave oscillators: while the master clock is capable to generate a self-sustained rhythm, the rhythms generated by the peripheral clocks are lost after several cycles because of desynchronization. To maintain proper phase relationships with each other, the slave oscillators in peripheral organs need to be coordinated by the central rhythm generator. This coordination is achieved by multiple direct and indirect output pathways of the central rhythm generator. According to current concepts, synchronization of peripheral clocks cannot be accomplished by a single entrainment signal, but requires a combination (cocktail) of signals. These cocktails appear to differ from one peripheral clock to the other. Moreover, peripheral clocks can be directly entrained by various external (environmental) stimuli. One of the most complex circadian systems is present in mammals; it drives the rhythm in locomotor activity, influences the sleep-wake cycle, and is involved in the control of body temperature, food intake, and metabolism. Moreover, the circadian system may affect the cell cycle. The central circadian rhythm generator of mammals is located in a distinct region of the brain, the bilaterally arranged suprachiasmatic nuclei (SCN) of the hypothalamus. Circadian rhythm generation in the SCN involves a molecular clockwork. The circadian rhythm generator in the SCN is entrained to the daily light/dark cycle. Light stimuli, acting as zeitgeber, are perceived by classical and novel photoreceptors in the retina and transmitted to the SCN via the retinohypothalamic tract (RHT), a distinct portion of the optic nerve. The RHT provides an essential input pathway to the SCN. Output pathways of the circadian rhythm generator in the SCN employ neuronal, neuroendocrine, and hormonal mechanisms. The final neuronal output pathway of the SCN is provided by the autonomic (sympathetic and parasympathetic) nervous system. An important neuroendocrine hand of the circadian system is melatonin which is produced night by night in the pineal gland under the control of the SCN. Melatonin represents a chronobiotic; it acts upon specific receptors, feeds back to the SCN, and modulates several autonomic functions. In addition to melatonin, glucocorticoids secreted from the cortex of the adrenal gland represent an important output signal of the circadian system. Glucocorticoids act on glucocorticoid receptors which are widely distributed in the body. Via these rather direct output pathways, the SCN sends timing signals to slave oscillators present in a variety of brain regions outside the SCN and in peripheral organs. SCN-derived timing signals are needed to maintain proper phase relationships among the multiple peripheral clocks, and the phase coherence in peripheral clocks is lost in SCN-lesioned animals. The SCN also provides indirect cues to the clocks in the periphery via its impact on the body temperature rhythm and the rest-activity rhythm which in turn drives the feeding rhythms. The feeding-fasting cycles which under normal conditions are in phase with the rest-activity rhythms appear to be dominant synchronizing signals for the peripheral clocks in the liver, kidney, pancreas, and heart. In these organs, the expression profiles of many circadian genes are influenced by the timing of food intake. This entrainment may be mediated by hormones secreted upon feeding or fasting, e.g., cholecystokinin, ghrelin, or leptin; by food metabolites, e.g., glucose, cholesterol, and fatty acids; by postprandial temperature elevations; and by the intracellular redox state ratio. The molecular clockwork in peripheral tissues controls circadian rhythms in metabolic and physiologic cell/organ function. The importance of molecular clocks is underlined by microarray studies showing that up to 20% of the genes expressed in peripheral organs (e.g., liver, muscle, adipose tissue) are rhythmic, suggesting that a considerable portion of the transcriptome is controlled by the circadian system. The rhythmically expressed genes encode proteins and enzymes involved in biosynthetic and metabolic processes such as lipid metabolism, glycolysis and gluconeogenesis, oxidative phosphorylation, and detoxification pathways. Notably, in many of these pathways, the rate-limiting enzymes are under circadian control. These data indicate a close interrelationship between the circadian system and energy metabolism. The circadian system may become altered or disrupted under various conditions. The most frequent reason for alteration of the circadian system in healthy people is the so-called jet lag occurring after rapid travel across a number of time zones. Moreover, disruptions of the circadian system are observed in numerous diseases. These include the familial advanced sleep phase syndrome, the delayed sleep phase syndrome, seasonal affective disorder, uni- and bipolar depression, autism spectrum disorders, Alzheimer's disease, Parkinson's disease, and Huntington,'s disease. Sleep disturbances in aging people can be partially attributed to age-related reduction in amplitude and phase advance of circadian rhythms. Finally, the close relationship between circadian and metabolic cycles suggests that the metabolic syndrome may be associated with disturbances of the circadian system.