PHYSIOLOGICAL SUBSTRATES OF A CIRCADIAN OSCILLATOR

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DESCRIPTION (Adapted fro applicant's abstract): Circadian rhythms order vital functions from the molecular to behavioral level. They are controlled by a biological clock that generates a near 24-h time base, into which afferent neuronal signals relaying information about environmental time and organismic state are integrated, and from which circadian rhythms are orchestrated. Our long-rang objective is to understand the cellular and molecular mechanisms that regulate the biological clock in suprachiasmatic nucleus (SCN) of the mammalian brain. Our extensive studies of the SCN brain slice preparation from rat have demonstrated that this circadian clock undergoes spontaneous circadian oscillation in SCN neuronal activity and concomitant modulation of sensitivities to phase-resetting stimuli. By monitoring the activity rhythm of the ensemble of SCN neurons, we have shown that the SCN clock regulates its own sensitivity to afferent signals in a circadian pattern that correlates with discrete periods in the environmental cycle of day and night. These changes persists in vitro, and thus are generated entirely within the SCN. Thus, the clock itself restricts activation of specific intracellular signaling pathways to specific time domains within the 24-h cycle. We propose to focus upon daytime mechanisms of SCN regulation. Photic and arousal stimuli have been proposed to initiate daytime clock resetting. The present proposal develops naturally from our finding that the SCN rhythm can be reset in the brain slice in the day, but not night, by treatments affecting cAMP pathways. Our specific aims include: 1) To identify the neurotransmitter(s) that activate cAMP; 2) To evaluate the behavioral context in which this pathway is activated; and 3) To characterize the relationship between cAMP stimulation and transcriptional activation. The results of these experiments will provide insights into integration of signals at this brain site, as well as to understanding of the cellular and molecular mechanisms by which these signals interact with the timekeeping mechanism. This research has basic relevance for understanding integrative brain function, for developing strategies for drug chronotherapeutics and for ameliorating internal desynchronization manifested as disordered hormonal and sleep patterns, depression and physiological decline with aging.