Roles for Astrocytes in Mediating Responses to Alcohol

描述(由申请人提供)：酒精在神经系统中有许多通过多个递质信号通路调节的作用。酒精的急性和慢性作用都通过未知的机制改变了与睡眠相关的行为。我们已经证明，星形胶质细胞是一种神经胶质细胞，通过依赖腺苷受体1(A1R)的机制来调节睡眠稳态。我们有新的证据表明，针对这一神经胶质通路的分子遗传操作也会影响酒精诱导的行为。我们认为酒精激活了腺苷依赖的星形胶质细胞和分子信号通路，正常情况下，这一通路有助于睡眠的动态平衡。我们最重要的假设是，腺苷的星形细胞来源介导了行为对酒精的敏感性，酒精中毒和睡眠障碍的共病涉及这一腺苷途径的长期扰动。该项目将分为三个部分。首先，我们将确定基于星形胶质细胞的信号通路，这些信号通路有助于酒精对行为的急性影响(目标1)。随后，我们将研究先前存在的睡眠稳态障碍如何影响酒精行为(目标2)，以及长期酒精暴露如何改变睡眠稳态(目标3)。尽管许多临床报告强调睡眠稳态和酒精行为之间的相关性，但很少有实验模型来探索这种关系。该项目的意义体现在开发新的实验模型和多种技术，这些技术将用于确定酒精行为和睡眠障碍之间的相互作用。下面描述的方法为治疗干预提供了独特的机会。这项拟议的研究采用创新的多学科整合方法，研究依赖星形胶质细胞的睡眠稳态作为酒精急性和慢性影响的关键媒介的参与。既然现在已知星形胶质细胞表达神经元中不表达的G蛋白偶联受体，结果也可能增强未来识别新靶点的潜力，以改善困扰正在康复的酗酒者的睡眠障碍。

DESCRIPTION (provided by applicant): Alcohol has numerous actions in the nervous system mediated through multiple transmitter signaling pathways. Both acute and chronic actions of alcohol modify sleep related behaviors through undefined mechanisms. We have shown that astrocytes, a type of glial cell, modulate sleep homeostasis by an adenosine receptor 1 (A1R)-dependent mechanism. We have novel evidence that molecular genetic manipulations directed at this glial pathway also impact alcohol-induced behaviors. We propose that alcohol activates the adenosine- dependent astrocytic cell and molecular signaling pathway that normally contributes to the homeostatic drive to sleep. Our overriding hypothesis is that an astrocytic source of adenosine mediates behavioral sensitivity to alcohol, and that the comorbidity of alcoholism and sleep disruptions involves long-term perturbations of this adenosine pathway. This project will be divided into three sections. Initially, we will identify the astrocyte-based signaling pathways that contribute to acute effects of alcohol on behavior (Aim 1). Subsequently, we will study how pre-existing impairments in sleep homeostasis impact alcohol behaviors (Aim 2), and how chronic alcohol exposure modifies sleep homeostasis (Aim 3). Despite numerous clinical reports that emphasize the correlation between sleep homeostasis and alcohol behaviors, few experimental models have been developed to explore this relationship. The significance of this project is reflected in the development of novel experimental models and multiple techniques that will be used to identify the interaction between alcohol behaviors and sleep impairments. The approaches described below offer distinct opportunities for therapeutic intervention. The proposed study uses an innovative integration of multidisciplinary approaches to study the involvement of the astrocyte-dependent sleep homeostat as a key mediator of acute and chronic effects of alcohol. Since astrocytes are now known to express G protein coupled receptors that are not expressed in neurons, results may also enhance the future potential to identify novel targets for ameliorating sleep impairments that haunt recovering alcoholics.