Neurologic Regulation of the SCN Circadian Clock

描述（由申请人提供）：由正常睡眠-觉醒周期的变化、不规则的工作模式或各种疾病状况引起的内部昼夜节律的去节律化，严重影响性能，增加事故风险，并促进心血管和精神疾病。改善昼夜节律紊乱的衰弱效应的进展在于理解昼夜节律调节的神经学基础。这项研究的总体目标是了解位于视交叉上核（SCN）中调节昼夜节律钟的神经递质系统。基于解剖学、药理学和行为学研究，神经肽Y（neuropeptide Y，NPY）被认为在调节昼夜节律计时系统中起关键作用。这些作用包括昼夜节律相位的行为控制和光夹带的调制。然而，到目前为止，即使是最基本的方面的神经肽Y的调节仍然是投机性的，因为方法还没有存在测量在SCN中的神经肽Y的体内释放。因此，影响神经肽Y释放和昼夜节律钟夹带的因素之间的功能关系尚不清楚。拟议的研究，结合新验证的微透析-质谱技术，用于测量行为自由的动物的SCN NPY释放，将提供有关昼夜节律系统中NPY调节的关键方面的首次信息。将评估光、行为和昼夜节律影响对SCN NPY释放的影响。此外，神经肽Y神经元的神经化学调节的特点。这些信息将为揭示NPY、5-羟色胺、谷氨酸和其他神经肽在生物钟调节中复杂、相互交织的作用提供必要的基础。研究的相关性：这项研究将扩展控制人类昼夜节律的神经机制的知识，包括那些与睡眠障碍和相关疾病有关的神经机制。这项工作的最终目标是帮助开发操纵生物钟机制的策略，以治疗这些使人衰弱的疾病。

DESCRIPTION (provided by applicant): Desynchronization of internal circadian rhythms, induced by shifts of the normal sleep-wake cycle, irregular work patterns or various disease conditions, profoundly affects performance, increases the risk of accident and promotes cardiovascular and psychiatric disorders. Progress towards ameliorating the debilitating effects of circadian desynchrony lies in understanding the neurologic basis for the regulation of circadian rhythms. The overarching goal of the proposed research is to understand the neurotransmitter systems that regulate the circadian clock located in the suprachiasmatic nuclei (SCN). Based upon anatomical, pharmacological and behavioral studies, neuropeptide Y (NPY) is thought to play critical roles in regulating the circadian timing system. These roles include the behavioral control of circadian rhythm phase, and the modulation of photic entrainment. To date, however, even the most fundamental aspects of NPY regulation remain speculative, because methodologies have not existed for measuring the in vivo release of NPY in the SCN. Thus, functional relationships between factors affecting NPY release and circadian clock entrainment are not understood. The proposed studies, incorporating the newly-validated microdialysis-mass spectrometric technique for measuring SCN NPY release from freely-behaving animals, will provide the first-ever information on critical aspects of NPY regulation in the circadian system. The effects of photic, behavioral and circadian influences on SCN NPY release will be evaluated. Moreover, the neurochemical regulation of NPY neurons will be characterized. This information will provide the groundwork necessary for unraveling the complex, intertwined roles of NPY, serotonin, glutamate and other neuropeptides in circadian clock regulation. Relevance of the research: This study will extend knowledge of the neurologic mechanisms that control human circadian timing, including those implicated in sleep disorders and associated diseases. The ultimate goal of this work is to aid in the development of strategies for manipulating circadian clock mechanisms to treat these debilitating conditions.