Neurologic Regulation of the SCN Circadian Clock

由正常睡眠-觉醒周期的变化引起的内部昼夜节律的去周期化， 不规则的工作模式或各种疾病状况，深刻影响业绩，增加 事故的风险，并促进心血管和精神疾病。进展 改善昼夜节律紊乱的衰弱效应在于了解神经系统的 调节昼夜节律的基础。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， 视交叉上核（SCN）。基于解剖学，药理学和行为学研究， 神经肽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的调制。 夹带然而，到目前为止，即使是最基本的神经肽Y调控方面仍然存在， 推测性的，因为还不存在用于测量NPY的体内释放的方法 在SCN。因此，影响NPY释放的因素与昼夜节律之间的功能关系 时钟夹带不被理解。拟议的研究，包括新验证的 微透析-质谱技术测定SCN-NPY从自由行为 动物，将提供有史以来第一次关于昼夜节律中NPY调节的关键方面的信息。 系统光、行为和昼夜节律对SCN NPY释放的影响将被研究。 评估。此外，神经肽Y神经元的神经化学调节的特点。这 信息将为解开复杂的、相互交织的角色提供必要的基础 NPY、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：这项研究将扩展神经机制的知识， 控制人类的昼夜节律，包括那些涉及睡眠障碍和相关的 疾病这项工作的最终目标是帮助开发操纵策略， 生物钟机制来治疗这些使人衰弱的病症。

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.