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The Functional Implications of Astrocytic GPCR-signaling on Alcohol Abuse

星形胶质细胞 GPCR 信号传导对酒精滥用的功能影响

基本信息

批准号：
10673854
负责人：
Simon Alexander Marshall
金额：
$ 37万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673854
关键词：
Addictive Behavior Address Adult Alcohol abuse Alcohol consumption Alcohol dependence Alcoholic Intoxication Alcohols American Amygdaloid structure Animal Model Anti-Anxiety Agents Area Astrocytes Behavior Behavioral Blood Blood alcohol level measurement Brain Injuries Cells Consummatory Behavior Consumption Darkness Data Dependence Development Economic Burden Ethanol Ethanol dependence Event G Protein-Coupled Receptor Signaling G alpha q Protein G-Protein-Coupled Receptors GLAST Protein Glial Fibrillary Acidic Protein Glutamate Transporter Glutamates Grant Healthcare Systems Heavy Drinking Immunohistochemistry Individual Inflammatory Influentials Interleukin-1 beta Interpersonal Relations Measures Mediating Modeling Mus National Institute on Alcohol Abuse and Alcoholism Nerve Degeneration Neurobiology Neuroimmune Neuroimmune system Neuronal Plasticity Operative Surgical Procedures Pathologic Pattern Population Procedures Production Property Quantitative Reverse Transcriptase PCR Recording of previous events Regulation Research Role Safety Sex Differences Signal Pathway Signal Transduction Societies Testing United States Virus Work alcohol behavior alcohol consequences alcohol effect alcohol exposure alcohol misuse alcohol pharmacology alcohol use disorder binge drinking cost cytokine density designer receptors exclusively activated by designer drugs drinking glial activation glutamatergic signaling health economics immunoreactivity innovation insight interest neurobiological mechanism neuroinflammation neurotransmission new therapeutic target novel novel therapeutics pharmacologic promoter receptor expression response sex social socioeconomics

项目摘要

Project Description Problematic alcohol consumption is a major health and socio-economic issue within the United States, but much of the economic burden and pathological consequences from alcohol misuse is associated with binge drinking. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has defined binge drinking as a pattern of drinking that results in a blood ethanol concentration (BEC) of greater than 80mg/dL. Repetitive binge drinking episodes greatly increases the likelihood of developing ethanol dependence. As such, it is critical to consider the neurobiological mechanisms that modulate binge drinking in order to develop novel therapeutic areas to curb alcohol misuse. The neuroimmune system has become of increasing interest as alcohol abuse can elicit neuroinflammatory cascades that can contribute to alcohol-induced neurodegeneration, but of more relevance to this study, alcohol can alter the neuroimmune systems role in neurotransmission and therein contribute to alcohol-related behaviors. This grant furthers our previous studies of binge-like alcohol’s effects on cytokines in the amygdala by specifically determining the impacts of alcohol misuse on astrocyte activation and expression patterns (Aim 1). Moreover, the impact of repeated binge-like drinking episodes on the permanence or plasticity of an altered astrocyte population will be ascertained (Aim 1). Secondly, these studies will determine the role of astrocytic signaling on ethanol consumption and alcohol- induced anxiolytic behavior (Aim 2), but Aim 3 will also determine whether alcohol’s impact on astrocytic glutamate and cytokine regulation is related to changes in alcohol consumption and pharmacologic properties. This will be accomplished by manipulating G-protein coupled receptors specifically in astrocytes using DREADDs under a GFAP promoter. Because sex-differences can alter neuroimmune responses, these studies will elucidate the impact of sex on both astrocytes effects on behavior and binge drinking on astrocytes. Together these three aims will test the overall hypothesis that there is a reciprocal and reinforcing relationship between alcohol and astrocyte activation associated with the impact of astrocytes on glutamatergic tone and cytokine production. These innovative studies will provide insight into the role of astrocytes in the transition to alcohol dependence, novel information regarding the impact of sex on alcohol-induced neuroimmune changes, and a shift in our understanding of the relationship between alcohol misuse and neuroimmune dysregulation.

项目描述酒精消费问题在美国是一个主要的健康和社会经济问题，酗酒造成的许多经济负担和病理后果都与酗酒有关喝酒国家酒精滥用和酒精中毒研究所（NIAAA）将酗酒定义为导致血液乙醇浓度（BEC）大于80 mg/dL的饮酒模式。重复酗酒事件大大增加了酒精依赖的可能性。因此，它是关键是要考虑调节酗酒的神经生物学机制，以开发新的治疗领域，以遏制酒精滥用。神经免疫系统已经变得越来越受关注，酒精滥用可引起神经炎症级联反应，神经变性，但更相关的是，这项研究，酒精可以改变神经免疫系统的作用，神经传递，并在其中促成酒精相关行为。这笔补助金促进了我们以前的研究通过专门确定酒精对杏仁核细胞因子的影响，误用星形胶质细胞活化和表达模式（目的1）。此外，反复暴饮暴食的影响饮酒事件对改变的星形胶质细胞群体的持久性或可塑性的影响将被确定（目的 1）。其次，这些研究将确定星形胶质细胞信号传导在乙醇消耗和酒精摄入中的作用。诱导抗焦虑行为（目标2），但目标3也将确定酒精对星形胶质细胞的影响是否谷氨酸和细胞因子调节与酒精消耗和药理学性质的变化有关。这将通过操纵G蛋白偶联受体，特别是在星形胶质细胞，在GFAP启动子下的DREADDs。由于性别差异可以改变神经免疫反应，这些研究将阐明性别对星形胶质细胞行为的影响和酗酒对星形胶质细胞的影响。这三个目标将共同检验一个总体假设，即存在一种相互加强的关系酒精和星形胶质细胞激活之间的关系与星形胶质细胞对神经元紧张性的影响有关，细胞因子产生。这些创新的研究将提供深入了解星形胶质细胞的作用，在过渡到酒精依赖，关于性对酒精诱导的神经免疫变化的影响的新信息，以及我们对酒精滥用和神经免疫失调之间关系的理解的转变。