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: 9064023
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064023
• 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 comorbidity; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; base; behavioral response; 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.

描述（由申请人提供）：酒精在神经系统中具有多种作用，通过多种递质信号通路介导。 酒精的急性和慢性作用都通过不确定的机制改变睡眠相关行为。我们已经表明，星形胶质细胞，一种类型的神经胶质细胞，调节睡眠稳态的腺苷受体1（A1R）依赖性机制。我们有新的证据表明，针对这种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，通常有助于睡眠的自我平衡驱动。我们最重要的假设是，星形胶质细胞来源的腺苷介导的行为对酒精的敏感性，以及酒精中毒和睡眠中断的共病涉及长期扰动这一腺苷途径。 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，有助于酒精对行为的急性影响（目标1）。随后，我们将研究预先存在的睡眠稳态障碍如何影响酒精行为（目标2），以及慢性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，但很少有实验模型被开发出来探索这种关系。该项目的重要性体现在开发新的实验模型和多种技术，用于识别酒精行为和睡眠障碍之间的相互作用。下文所述的方法为治疗干预提供了独特的机会。 该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导物的参与。由于星形胶质细胞现在已知表达G蛋白偶联受体，而这些受体在神经元中不表达，因此结果也可能增强未来确定改善睡眠障碍的新靶点的潜力，这些睡眠障碍困扰着正在康复的酗酒者。