Invited Review: A neural clockwork for encoding circadian time

Abstract

Many daily biological rhythms are governed by an innate timekeeping mechanism or clock. Endogenous, temperature-compensated circadian clocks have been localized to discrete sites within the nervous systems of a number of organisms. In mammals, the master circadian pacemaker is the bilaterally paired suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN is composed of multiple single cell oscillators that must synchronize to each other and the environmental light schedule. Other tissues, including those outside the nervous system, have also been shown to express autonomous circadian periodicities. This review examines 1) how intracellular regulatory molecules function in the oscillatory mechanism and in its entrainment to environmental cycles; 2) how individual SCN cells interact to create an integrated tissue pacemaker with coherent metabolic, electrical, and secretory rhythms; and 3) how such clock outputs are converted into temporal programs for the whole organism. suprachiasmatic nucleus; period; oscillator; pacemaker; photoperiod THE EARTH'S DAILY ROTATION about its axis has imposed potent selective pressures on organisms. The fundamental adaptation to the environmental day-night cycle is an endogenous 24-h clock that regulates biological processes in the temporal domain. This clock coordinates physiological events around local (geophysical) time, optimizing the economy of biological systems and allowing for a predictive, rather than purely reactive, homeostatic control. Circadian clocks contribute to the regulation of sleep and reproductive rhythms, seasonal behaviors, and celestial navigation. The practical importance of human circadian rhythmicity, as well as its consequences for health and disease, is now being realized. INVESTIGATING CIRCADIAN RHYTHMICITY AND LOCALIZING A PACEMAKER TO MAMMALIAN BRAINMany biological activities are restricted to specific times of day. In the absence of external timing cues, some of these processes remain rhythmic ("free run") with ϳ24-h (circadian) periods. The features of these self-sustaining oscillations have suggested the existence of an endogenous timekeeping mechanism. The circadian pacemaker receives input (afferent) pathways for synchronization (entrainment) to light-dark cycles and expresses its rhythmicity through output (efferent) pathways. The pacemaker works as a clock because its endogenous period is adjusted to the external 24-h period, primarily by light-induced phase shifts that reset the pacemaker's oscillation. Advances or delays occur because the pacemaker is differentially sensitive to light exposure at different times in its free-running circadian cycle; this rhythm of light sensitivity can be quantified as a "phase-response curve" (PRC). Variations in photic sensitivity, in concert with changes in the pacemaker's endogenous period and amplitude, can dramatically affect the temporal sequencing of clock-controlled events.In mammals, a circadian pacemaker has been localized to the suprachiasmatic nucleus (SCN). The body of evidence identi...

Minireview: The Neuroendocrinology of the Suprachiasmatic Nucleus as a Conductor of Body Time in Mammals

“…In this view, coherent rhythmicity is seen at the level of the whole tissue and is an emergent property of all these individual oscillators working together in synchrony. Individual SCN cells have circadian rhythms in electrical activity, but the period and phase differ among cells (20,21). This finding is consistent with the possibility that all SCN neurons are oscillators (reviewed in Refs.…”

Biochemical and molecular studies using human autopsy brain tissue

“…Cycles are nearly universal, and occur in phylogenies as diverse as cyanobacteria, fungi, plants and animals (Pittendrigh 1993;Taghert 2001;Albrecht 2002;Herzog and Schwartz 2002;Reppert and Weaver 2002). Rhythms are generated internally even in relatively constant environmental conditions.…”

Age-related disruptions of circadian rhythm and memory in the senescence-accelerated mouse (SAMP8)

“…With respect to the former property, it is the endogenous (self-sustaining) nature of circadian rhythms that engenders an internal clock. With respect to the latter property, the major external cue that serves to synchronize the circadian rhythms of humans and other mammals is light, but almost any periodic event can act as a Zeitgeber ("time-giver").Research on the biological basis of circadian rhythms in humans and other mammals implicates the suprachiasmatic nucleus (SCN) of the anterior hypothalamus as the brain region responsible for the generation and maintenance of circadian rhythms (Herzog and Schwartz 2002;Klein et al 1991). Support for the SCN as the master circadian clock comes from a wide variety of sources.…”

“…Research on the biological basis of circadian rhythms in humans and other mammals implicates the suprachiasmatic nucleus (SCN) of the anterior hypothalamus as the brain region responsible for the generation and maintenance of circadian rhythms (Herzog and Schwartz 2002;Klein et al 1991). Support for the SCN as the master circadian clock comes from a wide variety of sources.…”