Neurologic Regulation of the SCN Circadian Clock

描述(申请人提供)：由正常睡眠-清醒周期的改变、不规律的工作模式或各种疾病条件引起的内部昼夜节律的不同步，严重影响表现，增加事故风险，并促进心血管和精神障碍。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。这项拟议研究的首要目标是了解调节视交叉上核(SCN)生物钟的神经递质系统。根据解剖学、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。这些作用包括对昼夜节律阶段的行为控制，以及对光携带的调节。然而，到目前为止，即使是NPY调控的最基本的方面也仍然是推测的，因为还没有方法来测量在SCN中NPY的体内释放。因此，影响NPY释放的因素和昼夜节律时钟夹带之间的功能关系尚不清楚。这项拟议的研究结合了新验证的微透析-质谱学技术来测量自由行为动物的SCN NPY释放，将首次提供关于昼夜节律系统中NPY调节的关键方面的信息。将评估光、行为和昼夜节律对SCN NPY释放的影响。此外，还将描述NPY神经元的神经化学调节。这些信息将为解开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机制。这项工作的最终目标是帮助制定策略，操纵生物钟机制来治疗这些衰弱的疾病。

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.