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: 8668830
• 负责人: PHILIP G HAYDON
• 金额: $ 28.92万
• 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/8668830
• 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.

描述（由申请人提供）：酒精在通过多个发射器信号通路介导的神经系统中有许多作用。 酒精的急性和慢性作用都通过不确定的机制改变了与睡眠相关的行为。我们已经表明，星形胶质细胞是一种神经胶质细胞，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，针对这种神经胶质途径的分子遗传操纵也影响了酒精诱导的行为。我们建议酒精激活依赖性腺苷的星形胶质细胞和分子信号通路，通常有助于稳态驱动器。我们的压倒性假设是，腺苷的星形细胞来源介导了对酒精的行为敏感性，酒精中毒和睡眠中断的合并症涉及这种腺苷途径的长期扰动。 该项目将分为三个部分。最初，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（AIM 1）。随后，我们将研究睡眠稳态的预先存在障碍如何影响酒精行为（AIM 2），以及长期酒精暴露如何改变睡眠体内稳态（AIM 3）。尽管许多临床报道强调了睡眠稳态与酒精行为之间的相关性，但很少开发实验模型来探索这种关系。该项目的意义反映在新型实验模型和多种技术的开发中，这些技术将用于确定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不同的机会。 拟议的研究使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体内体的参与，作为酒精急性和慢性作用的关键介体。由于现在已知星形胶质细胞表达在神经元中未表达的G蛋白偶联受体，因此结果还可能增强未来的潜力，以确定改善睡眠不足的新靶标，以困扰着酗酒者。