Neurologic Regulation of the SCN Circadian Clock

正常睡眠-觉醒/光-暗周期的改变、不规律的工作模式或各种疾病状态引起的内部昼夜节律的去同步，对人类的健康和表现产生不利影响。改善昼夜节律去同步性的衰弱作用的进展在于理解昼夜节律调节的神经学基础。这项研究的主要目标是描述调节视交叉上核(SCN)中生物钟的神经系统。根据解剖学、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中的光携带输入，以及控制昼夜节律的相位。然而，到目前为止，关于5-羟色胺效应的基本方面的信息，如它在行为昼夜节律夹带中的作用部位(S)，以及调节大脑昼夜节律系统中5-羟色胺释放的机制，人们还知之甚少。建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。本研究的第一个目的是利用体内微透析法研究行为诱导的5-羟色胺释放到SCN和膝间小叶的中缝间机制。躯体树突状自体受体和5-HT7和GABAA受体在这一机制中的关键作用将被确定。第二个目标是通过分析行为学和5-羟色胺激动剂诱导的昼夜节律时钟重置来研究5-羟色胺在脊髓核内的直接时相重置作用。SCN 5-HT7受体在调节行为相移和SCN Per mRNA水平变化中的作用将使用新获得的该受体的特异性拮抗剂进行评估。这些研究将有助于建立一个概念性的框架，将体内5-羟色胺的释放与SCN昼夜节律时钟的光和非光夹带联系起来。这些研究的结果可能导致操纵5-羟色胺能系统的策略，以对抗昼夜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.