Ethanol Effects on the Mammalian Circadian Clock

具体目标 这项建议继续我们的研究乙醇对哺乳动物生物钟的影响 位于视交叉上核（SCN）。酒精的使用、滥用和戒断 对睡眠和昼夜节律有着深远的影响。酒精对这两个过程的影响可能 是紧密交织在一起的，因为昼夜节律功能的中断是许多疾病的主要原因。 睡眠不规律我们研究的长期目标是更好地了解神经系统 过程有助于这些睡眠问题的病因，特别是侧重于作用 昼夜节律我们的合作研究表明，乙醇抑制光相， 在体内和体外重置SCN生物钟。本RO 1的目标 一项建议是确定乙醇急性效应的细胞机制， 扩大我们的研究，调查慢性酒精和酒精戒断的影响。的 我们合作的主要优势是我们能够在体内和体内相互补充， 利用每种方法的独特方面的体外实验。我们的中央 一种假说是乙醇抑制核心SCN神经元中的谷氨酸信号，随着时间的推移， 会导致肾上腺素能活动上调我们进行拟议研究的理由是， 确定乙醇调节生物钟的细胞机制将 从而对可能预防或克服这种使人衰弱的疾病的治疗方法产生新的见解。 因此，我们建议实现以下具体目标： 具体目标1。确定乙醇对光/光化学的影响的时间依赖性变化。 SCN中的谷氨酸信号传导：急性与耐受性与慢性与戒断。这些 实验将描述乙醇对SCN生物钟的影响， 监测行为和电生理（体内和体外）节律，以及这些 影响取决于乙醇暴露的持续时间。 具体目标2。确定乙醇在SCN中作用的细胞机制。这些 实验将评估乙醇对体内SCN神经肽释放模式的影响， 并研究乙醇抑制谷氨酸诱导的细胞机制。 体外相位重置。 具体目标3。确定乙醇如何影响非光相位重置。这些 实验将评估急性和慢性乙醇以及乙醇戒断对 在体内和体外的多巴胺能、GABA能和NPY能的相位重置，并探测 这些影响发生的机制和位置。

SPECIFIC AIMS This proposal continues our investigation of ethanol effects on the mammalian circadian clock located in the suprachiasmatic nucleus (SCN). Alcohol use, abuse and withdrawal have profound effects on sleep and circadian rhythms. Alcohol effects on these two processes likely are closely intertwined since disruptions in circadian functioning are major causes of many sleep irregularities. The long-term goal of our research is to better understand the neural processes contributing to the etiology of these sleep problems, specifically focusing on the role circadian rhythmsOur collaborative research shows that ethanol inhibits photic phase resetting of the SCN circadian clock in vivo and in vitro. The objective of this RO1 proposal is to identify the cellular mechanisms underlying the acute effects of ethanol, and to expand our research to investigate the effects of chronic alcohol and alcohol withdrawal. The major advantage of our collaboration is our ability to interweave complementary in vivo and in vitro experiments that take advantage of the unique aspects of each approach. Our central hypothesis is that ethanol inhibits glutamate signaling in core SCN neurons, which over time leads to up-regulated glutamatergic activity. Our rationale for the proposed studies is that identifying the cellular mechanisms through which ethanol modulates the circadian clock will lead to new insights on treatments that may prevent or overcome this debilitating disease. Therefore, we proposed to pursue the following specific aims: Specific Aim 1. Determine time-dependent changes in ethanol effects on photic/ glutamate signaling in the SCN: acute vs. tolerance vs. chronic vs. withdrawal. These experiments will characterize the effects of ethanol on the SCN circadian clock through monitoring behavioral and electrophysiological (in vivo and in vitro) rhythms, and how these effects vary depending on the duration of ethanol exposure. Specific Aim 2. Determine the cellular mechanisms of ethanol actions in the SCN. These experiments will assess the effects of ethanol on in vivo SCN neuropeptide release patterns, and investigate the cellular mechanisms through which ethanol inhibits glutamate-induced phase resetting in vitro. Specific Aim 3. Determine how ethanol affects non-photic phase resetting. These experiments will assess the effects of acute and chronic ethanol, and ethanol withdrawal, on serotonergic, GABAergic, and NPYergic phase resetting in vivo and in vitro, and probe the mechanisms and locations through which these effects occur.