Neurologic Regulation of the SCN Circadian Clock

由正常睡眠-觉醒周期的改变引起的内部昼夜节律的去同步， 不规律的工作模式或各种疾病状况，深刻影响工作表现，增加 增加发生意外的风险，并促进心血管和精神疾病。取得的进展 改善昼夜节律失同步性的衰弱作用在于对神经学的理解 昼夜节律调节的基础。拟议研究的总体目标是 为了了解调节生物钟的神经递质系统位于 视交叉上核(SCN)基于解剖学、药理学和行为学的研究， 神经肽Y(NPY)被认为在调节昼夜节律系统中起着关键作用。 这些作用包括昼夜节律相位的行为控制和光的调节 夹带。然而，到目前为止，即使是NPY监管的最基本方面也仍然存在 推测，因为目前还没有测量NPY体内释放的方法 在SCN中。因此，影响NPY释放的因素与昼夜节律之间的函数关系 时钟夹带是不被理解的。拟议的研究，纳入了新验证的 微渗析-质谱法测定SCN NPY的自由行为释放 动物，将首次提供有关昼夜节律中NPY调节的关键方面的信息 系统。光、行为和昼夜节律的影响对SCN NPY释放的影响将是 已评估。此外，还将描述NPY神经元的神经化学调节。这 信息将为解开复杂、相互交织的角色提供必要的基础 神经肽Y、5-羟色胺、谷氨酸等神经肽在生物钟调节中的作用。 研究的相关性：这项研究将扩展对神经机制的知识， 控制人类的昼夜节律，包括那些与睡眠障碍有关的和与之相关的 疾病。这项工作的最终目标是帮助制定操纵策略 生物钟机制来治疗这些衰弱的情况。

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 NPYrelease 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.