The roles of GABA receptor subunits in circadian rhythms in GABA responsiveness in the suprachiasmatic nucleus

 描述(申请人提供)：生物钟在几乎所有的行为和生理中产生内源性节律。扰乱这些生物钟对日常明暗循环的影响，会导致大量的代谢、精神和神经紊乱。要了解这些疾病的病因是如何由夹带中断引起的，需要了解位于视交叉上核(SCN)的主生物钟中控制夹带的神经机制。这项拟议研究的总体目标是确定SCN对环境明暗循环的潜在神经机制。在理解组成分子时钟的翻译和转录反馈环方面已经取得了很大的进展，但在携带过程中改变时钟的特定神经化学信号还没有被很好地理解。然而，很明显，GABA是这些神经化学信号之一，对SCN的携带至关重要。GABA对SCN的夹带的影响是阶段特定的，然而这种影响模式背后的机制尚不清楚。这些研究将检验以下假设：在夹带过程中，-2突触受体和GABA-突触外受体之间的表达和功能的昼夜振荡是SCN对GABA的昼夜时相特异性反应的基础，并且这些受体以不同的方式介导了SCN中时钟基因周期的诱导。在更大的范围内，这些研究将提供关于GABA信号和GABAA受体亚型相互作用的新信息，这些信息可能与GABA在整个中枢神经系统的作用有关。由于许多针对GABA系统的药物被用于治疗从焦虑症到癫痫等各种疾病，因此了解GABA在大脑中的作用具有重要的临床意义。此外，我所接受的培训 完成这些研究将极大地加速我作为一名科学家的发展，并使我成为一所研究密集型大学的独立调查员。

 DESCRIPTION (provided by applicant): Circadian clocks generate endogenous rhythms in nearly all behavior and physiology. Disruption of the entrainment of these clocks to the daily light-dark cycle contributes to a multitude of metabolic, psychiatric, and neurologic disorders. Understanding how the etiology of these disorders is produced by disruptions in entrainment will require understanding the neural mechanisms controlling entrainment in the master circadian clock, which is located in the suprachiasmatic nucleus (SCN). The overall goal of the proposed research is identify neural mechanisms underlying the entrainment of the SCN to the environmental light-dark cycle. Great progress has been made in understanding the translational and transcriptional feedback loops that comprise the molecular clock, yet the specific neurochemical signals that shift the clock during entrainment are not well understood. However, it is clear that GABA is one of these neurochemical signals critical to entrainment of the SCN. The effects of GABA on entrainment of the SCN are phase-specific, however the mechanism underlying this pattern of effects is not known. These studies will test the hypotheses that circadian oscillations in the expression and function between the GABAA2 synaptic receptor and the GABAA extrasynaptic receptor underlie the circadian phase-specific responses of the SCN to GABA during entrainment, and that these receptors differentially mediate induction of the clock gene Period in the SCN. On a larger scale, these studies will provide new information on GABA signaling and the interaction of GABAA receptor subtypes that may be relevant to the action of GABA throughout the CNS. Because many drugs that target the GABA system are used to treat diseases ranging from anxiety disorders to epilepsy, it is clinically important to understand how GABA acts in the brain. Additionally, the training that I will receive in completion of these studies will significantly accelerate my development as a scientist and springboard me to reach my goal as an independent investigator at a research-intensive university.