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、不规律的工作模式或各种疾病状况引起的内部昼夜节律的不同步，严重影响工作表现，增加事故风险，并促进心血管和精神疾病。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了解调节位于视交叉上核（SCN）的生物钟的神经递质系统。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阶段的行为控制和光夹带的调节。然而，到目前为止，即使是NPY调控的最基本方面仍然是推测性的，因为尚不存在测量SCN中NPY在体内释放的方法。因此，影响NPY释放和生物钟夹带的因素之间的功能关系尚不清楚。拟议的研究结合了新验证的微透析-质谱技术，用于测量自由行为动物的SCN NPY释放，将首次提供有关昼夜节律系统中NPY调节关键方面的信息。将评估光、行为和昼夜节律对SCN NPY释放的影响。此外，NPY神经元的神经化学调节将被表征。这一信息将为揭示NPY、血清素、谷氨酸和其他神经肽在生物钟调节中的复杂、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控制昼夜节律机制的策略，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.