Neurologic Regulation of the SCN Circadian Clock

由正常睡眠-觉醒/光-暗周期的变化、不规则的工作模式或各种疾病状态引起的内部昼夜节律的不同步，对人类的健康和表现产生不利影响。改善昼夜节律不同步的衰弱效应的进展在于理解昼夜节律调节的神经学基础。提出的研究的总体目标是表征调节位于视交叉上核（SCN）的生物钟的神经系统。基于解剖学、药理学和行为学的研究，5-羟色胺（5- HT）与昼夜节律的调节密切相关。它的作用包括调节SCN的光携带输入和控制昼夜节律阶段。然而，迄今为止，关于5-羟色胺作用的基本方面的信息，如其在行为昼夜节律干扰中的作用位点，以及调节大脑昼夜节律系统中5-羟色胺释放的机制，人们知之甚少。拟议的研究旨在提供与这些问题有关的5-羟色胺作用方面的基本信息。该研究的第一个目标是表征通过体内微透析评估行为诱导的5-HT释放到SCN和间束小叶（IGL）的跨叶机制。躯体树突中缝自受体、5-HT7和GABAA受体在这一机制中的关键作用将被确定。第二个目标将是通过分析行为和5-HT激动剂诱导的生物钟重置来研究5-HT在SCN中的直接相位重置作用。SCN 5-HT7受体在介导行为相移和SCN Per mRNA水平变化中的作用将使用该受体的新特异性拮抗剂进行评估。这些研究将有助于建立体内5-羟色胺释放与SCN生物钟的光和非光携带相关的概念框架。这些研究的结果可能导致操纵血清素能系统的策略，以对抗昼夜节律不同步的破坏性影响。

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.