Neurologic Regulation of the SCN Circadian Clock

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Desynchronization of internal circadian rhythms, induced by shifts of the normal sleep-wake/light-dark cycles, irregular work patterns or various disease states, adversely affects human health and performance. Progress towards ameliorating the debilitating effects of circadian desynchrony lies in understanding the neurologic basis for the regulation of circadian rhythms. The broad goal or the proposes studies is to characterize the neural systems that regulate the circadian clock located in the suprachiasmatic nuclei (SCN). Based upon anatomical, pharmacological and behavioral studies, serotonin (5- HT) is strongly implicated in the regulation of circadian timekeeping. Its roles include the modulation of photic entraining input in the SCN, and the control of circadian rhythm phase. To date, however, information on fundamental aspects of 5-HT effects such as the site(s) of its action in behavioral circadian entrainment, and mechanisms regulating 5-HT release in the brain circadian system are poorly understood. The proposed studies are designed to provide basic information on aspects of 5-HT action relating to these questions. The first goal of the research is to characterize the inter-raphe mechanism mediating behaviorally-induced 5-HT release into the SCN and intergeniculate leaflet (IGL) evaluated using in vivo microdialysis. Critical roles of somatodendritic raphe autoreceptors and 5-HT7 and GABAA receptors in this mechanism will be determined. The second goal will be to study the direct phase-resetting actions of 5-HT in the SCN by analyzing behavioral and 5-HT agonist induced circadian clock resetting. The role of the SCN 5-HT7 receptor in mediating behavioral phase- shifting and changes in SCN Per mRNA levels will be evaluated using newly available specific antagonists of this receptor. These studies will contribute to a conceptual framework for relating in vivo 5-HT release to the photic and non-photic entrainment of the SCN circadian clock. Results from these studies could lead to strategies for manipulating the serotonergic system to counter the disruptive effects of circadian desynchrony.