Roles for Astrocytes in Mediating Responses to Alcohol

星形胶质细胞在介导酒精反应中的作用

• 批准号: 8256163
• 负责人: PHILIP G HAYDON
• 金额: $ 29.82万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256163
• 关键词: Acute; Adenosine; Adolescent; Adverse effects; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Alcoholism; Alcohols; Astrocytes; Behavior; Behavioral; Cells; Chronic; Clinical; Comorbidity; Data; Development; Dopamine; Electroencephalography; Electromyography; Electrophysiology (science); Experimental Models; Future; G-Protein-Coupled Receptors; Glutamates; Homeostasis; Human; Impairment; Mediating; Mediator of activation protein; Microdialysis; Modeling; Molecular; Molecular Genetics; Mus; Nervous system structure; Neuroglia; Neurons; Nucleoside Transporter; Outcome Study; Pathway interactions; Peripheral; Pharmacology; Phenotype; Property; Purinergic P1 Receptors; Reporting; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Source; Synaptic Transmission; Techniques; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; base; extracellular; gamma-Aminobutyric Acid; genetic manipulation; in vivo; innovation; interdisciplinary approach; novel; problem drinker; receptor; uptake

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. PUBLIC HEALTH RELEVANCE: In this study we will test our hypothesis that behavioral actions of alcohol are mediated through glial-based signaling pathways that regulate neuronal synaptic transmission and sleep. Since astrocytes, the subtype of glia under study, are known to express G protein-coupled receptors that are not expressed in neurons, the results of this study have the potential to help identify novel targets for ameliorating the sleep impairments suffered by recovering alcoholics.

描述（由申请人提供）：酒精通过多种递质信号传导途径在神经系统中发挥多种作用。 酒精的急性和慢性作用都会通过不确定的机制改变与睡眠相关的行为。我们已经证明，星形胶质细胞（一种神经胶质细胞）通过腺苷受体 1 (A1R) 依赖性机制调节睡眠稳态。我们有新的证据表明，针对该神经胶质途径的分子遗传操作也会影响酒精诱发的行为。我们认为，酒精会激活腺苷依赖性星形胶质细胞和分子信号传导途径，该途径通常有助于睡眠的稳态驱动。我们最重要的假设是，腺苷的星形细胞来源介导对酒精的行为敏感性，并且酗酒和睡眠中断的共病涉及该腺苷途径的长期扰动。 该项目将分为三个部分。首先，我们将确定导致酒精对行为产生急性影响的基于星形胶质细胞的信号通路（目标 1）。随后，我们将研究预先存在的睡眠稳态损伤如何影响酒精行为（目标 2），以及长期酒精暴露如何改变睡眠稳态（目标 3）。尽管大量临床报告强调睡眠稳态与酒精行为之间的相关性，但很少有实验模型被开发来探索这种关系。该项目的重要性体现在新型实验模型和多种技术的开发上，这些模型和技术将用于识别酒精行为与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。 拟议的研究采用多学科方法的创新整合来研究星形胶质细胞依赖性睡眠稳态作为酒精急性和慢性影响的关键介质的参与。由于目前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，因此结果还可能增强未来确定改善睡眠障碍的新靶标的潜力，这些睡眠障碍困扰着正在康复的酗酒者。 公共健康相关性：在这项研究中，我们将检验我们的假设，即酒精的行为作用是通过调节神经元突触传递和睡眠的神经胶质信号通路介导的。由于已知星形胶质细胞（正在研究的神经胶质细胞亚型）表达神经元中不表达的 G 蛋白偶联受体，因此这项研究的结果有可能帮助确定新的靶点，以改善戒酒者所遭受的睡眠障碍。