[Understanding the action of the circadian clock: from phenomenologic ideas to molecular activity]

Abstract

The focus of the present review is to present recent studies of the mammalian circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The main questions in circadian neuroscience are: how many oscillators are implicated, how are their daily oscillations generated and synchronized to the external environment and how does the central clock send timed signals to the whole organism. The review is introduced by a presentation of circadian system properties and by a description of the responses to manipulations of the main entraining factor, i.e. the light-dark cycle. The anatomy of the SCN and its major afferents from the retina (glutamate, Substance P), raphe (serotonin) and intergeniculate leaflet (neuropeptide Y) of the thalamus are presented with a special emphasis on the interaction of these inputs with the circadian timekeeping mechanism. The arguments related to the issue of whether the retina contain an endogenous oscillator are exposed. What is known of the endogenous mechanism(s) of this small structure containing 10,000 or so "self-oscillating neurons" is reviewed through: i) the anatomical distribution and functional significance of clock-peptides (VIP, PHI, GRP, VP or SS), ii) the putative involvement of the SCN astrocytic population in coordinating neuronal activities, iii) the various aspects of cellular activity (electrical activity, energy metabolism, protein or peptide synthesis) and iv) the participation of immediate early genes in light-driven phase shifts. The present understanding of molecular timekeeping mechanism is exposed in light of the growing list of candidate clock-genes described within the SCN as well as in peripheral tissues of mammals and also in the clock-systems of phylogenetically lower species. Efferents from the SCN are also discussed with an interest toward understanding how the central circadian information is transmitted to the rest of the brain in order to impulse or/and coordinate the numerous rhythmic activities of the organism. Finally, cellular disturbances in peptide expression or content, reduction in the amplitude of a given functional index or even astrocytic proliferation are viewed along the line of pathologies observed with aging.