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.

项目描述有问题的饮酒是美国的一个重大健康和社会经济问题，但是滥用酒精造成的大部分经济负担和病理后果都与酗酒有关美国国家酒精滥用和酒精中毒研究所 (NIAAA) 将酗酒定义为一种行为。导致血液乙醇浓度 (BEC) 重复超过 80 毫克/分升的饮酒方式。暴饮暴食大大增加了产生乙醇依赖的可能性。考虑调节酗酒的神经生物学机制至关重要，以便开发新的抑制酒精滥用的治疗领域越来越受到人们的关注。酗酒会引发神经炎症级联反应，从而导致酒精诱发的神经炎症级联反应神经退行性疾病，但与本研究更相关的是，酒精可以改变神经免疫系统的作用神经传递及其促进酒精相关行为的研究进一步推进了我们之前的研究。通过具体确定酒精的影响，研究酗酒对杏仁核细胞因子的影响误用对星形胶质细胞的激活和表达模式（目标1）此外，重复暴饮暴食的影响。将确定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（目标 1).其次，这些研究将确定星形细胞信号传导对乙醇消耗和酒精的作用诱导抗焦虑行为（目标 2），但目标 3 还将确定酒精是否对星形胶质细胞的影响谷氨酸和细胞因子的调节与饮酒和药理学特性的变化有关。这将通过使用专门操纵星形胶质细胞中的 G 蛋白偶联受体来实现由于性别差异可以改变神经免疫反应，这些研究在 GFAP 启动子下产生了 DREADD。将阐明性对星形胶质细胞的影响对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总体假设，即存在相互增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谷氨酸能张力的影响有关这些创新研究将深入了解星形胶质细胞在向细胞因子的转变中的作用。酒精依赖，关于性对酒精引起的神经免疫变化影响的新信息，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。