Neurobiology of circadian systems.

Time is a dimension tightly associated with the biology of living species. There are cycles of varied lengths in biological activities, from very short (ultradian) rhythms to rhythms with a period of approximately one day (circadian) and rhythms with longer cycles, of a week, a month, a season, or even longer. These rhythms are generated by endogenous biological clocks, i.e. time-keeping structures, rather than being passive reactions to external fluctuations. In mammals, the suprachiasmatic nucleus (SCN) is the major pacemaker. The pineal gland, which secretes melatonin, is the major pacemaker in other phyla. There also exist biological clocks generating circadian rhythms in peripheral tissues, for example the liver. A series of clock genes generates the rhythm through positive and negative feedback effect of proteins on their own synthesis, and this system oscillates with a circadian period. External factors serve as indicators of the astronomical (solar) time and are called zeitgebers, literally time-givers. Light is the major zeitgeber, which resets daily the SCN circadian clock. In the absence of zeitgebers, the circadian rhythm is said to be free running; it has a period that differs from 24 hours. The SCN, together with peripheral clocks, enables a time-related homeostasis, which can become disorganized in its regulation by external factors (light, social activities, food intake), in the coordination and relative phase position of rhythms, or in other ways. Disturbances of rhythms are found in everyday life (jet lag, shift work), in sleep disorders, and in several psychiatric disorders including affective disorders. As almost all physiological and behavioural functions in humans occur on a rhythmic basis, the possibility that advances, delays or desynchronization of circadian rhythms might participate in neurological and psychiatric disorders has been a theme of research. In affective disorders, a decreased circadian amplitude of several rhythms as well as a phase advance or delay have been described, leading to hypotheses about changes in biological clocks themselves or in their sensitivity to environmental factors, such as light or social cues. Molecular genetics studies have suggested the involvement of circadian clock genes, but no tight association has yet been found. Agomelatine is an antidepressant, agonist at melatonergic MT(1), MT(2) receptors and antagonist at 5-HT(2C) receptors, and is able to phase advance circadian rhythms in humans. The fact that non-pharmacological (light therapy, sleep deprivation, rhythm therapy) and pharmacological (lithium, antidepressants, agomelatine) therapies of affective disorders influence circadian rhythms indicates that biological clocks play a role in the pathophysiology of these disorders.