NEUROLOGIC REGULATION OF THE SCN CIRCADIAN CLOCK

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DESCRIPTION: (Applicant's abstract) Desynchronization of normal circadian patterns, induced by shifts of the normal sleep-wake cycle, irregular work patterns or various disease conditions, is known to adversely affect productivity, increase the risks of accident and affect emotional state. Progress towards developing treatments for ameliorating the debilitating effects of circadian desynchrony lies in understanding the neurological basis for the regulation of endogenous circadian rhythms. The broad goal of the present studies is to characterize the regulatory roles of specific neurotransmitters associated with the circadian clock located within the suprachiasmatic nuclei (SCN). Based primarily on pharmacological and lesioning studies, the monoamine transmitter, serotonin (5-HT), has been implicated as a major participant in the regulation of the daily circadian sleep-activity cycle as well as other circadian rhythms. To date, however, the action of endogenous 5-HT in the SCN circadian clock has not been directly studied. This has become a major shortcoming in understanding the basic biology of 5-HT action in the SCN clock. The proposed studies, therefore, are designed to study the physiology of the serotonergic projection to the SCN from the raphe nuclei of the Syrian hamster. The specific objectives are as follows: 1) to characterize the in vivo dynamics of 5-HT release in the SCN induced by electrical stimulation of specific raphe nuclei: 2) to precisely manipulate raphe activity to characterize the modulatory effects of endogenous 5-HT on photic signalling processes in the SCN )including light-induced immediate-early gene activation and phase-shift of the free-running activity rhythm) and phase resetting of the clock; and 3) to assess the 24 hour profile of 5-HT release in the SCN region of freely-moving animals under light entrained and free-running (constant light or dark) conditions to determine relationships between photic environment, neurological state and serotonergic activity in the SCN. Rates of 5-HT release will be measured during activity-induced phase shifts to specifically determine if 5-HT mediates non-photic shifts in circadian clock phase. Results from these experiments could lead to strategies for manipulating the serotonergic system to counter the disruptive effects of circadian desynchrony.