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

 描述（由申请人提供）：生物钟在几乎所有行为和生理学中产生内源性节律。这些生物钟对日常明暗循环的干扰会导致许多代谢、精神和神经疾病。了解这些疾病的病因是如何产生的干扰夹带将需要了解的神经机制控制夹带在主昼夜节律钟，这是位于视交叉上核（SCN）。这项研究的总体目标是确定SCN夹带到环境光暗周期的神经机制。在理解构成分子钟的翻译和转录反馈回路方面已经取得了很大进展，但在夹带期间改变时钟的特定神经化学信号还没有得到很好的理解。然而，很明显，GABA是对SCN夹带至关重要的神经化学信号之一。GABA对SCN夹带的影响是阶段特异性的，然而这种影响模式的机制尚不清楚。这些研究将测试的假设，昼夜节律振荡的表达和功能之间的GABAA β 2突触受体和GABAA β突触外受体的基础上的昼夜节律相位特异性反应的SCN GABA在夹带期间，这些受体差异介导的时钟基因周期在SCN的诱导。在更大的范围内，这些研究将提供有关GABA信号传导和GABAA受体亚型相互作用的新信息，这些信息可能与GABA在整个CNS中的作用有关。由于许多靶向GABA系统的药物被用于治疗从焦虑症到癫痫的疾病，因此了解GABA在大脑中的作用在临床上非常重要。此外，我所接受的培训 完成这些研究将大大加速我作为一名科学家的发展，并帮助我实现在一所研究型大学成为一名独立研究者的目标。

 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.