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主要健康和社会经济问题，但滥用酒精的许多经济烧伤和病理后果与暴饮暴食有关喝。美国国家酒精滥用与酒精中毒研究所（NIAAA）已将Benge饮酒定义为饮酒模式导致血液乙醇浓度（BEC）大于80mg/dl。重复暴饮暴食发作大大增加了发展乙醇依赖性的可能性。因此，是考虑调节暴饮暴食以开发新颖的神经生物学机制至关重要治疗区域以遏制滥用酒精。神经免疫系统已成为越来越多的兴趣酗酒会引起神经炎症性级联反应，可以导致酒精引起的神经变性，但与这项研究更相关，酒精可以改变神经免疫系统在神经传递及其有助于与酒精相关的行为。这项赠款进一步发展了我们以前的研究通过专门确定酒精的影响滥用星形胶质细胞激活和表达模式（AIM 1）。此外，重复的暴饮暴食的影响将确定关于变化的星形胶质细胞种群的永久性或可塑性的饮酒事件（AIM 1）。其次，这些研究将确定星形胶质细胞信号传导对乙醇消耗和酒精的作用诱发抗焦虑行为（AIM 2），但AIM 3也将决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饮酒和药物特性的变化有关。这将是通过专门在星形胶质细胞中操纵G蛋白偶联受体来完成的 Dreadds在GFAP启动子下。由于性别差异可以改变神经免疫反应，因此这些研究将阐明性别对两个星形胶质细胞对行为的影响和宾格饮酒对星形胶质细胞的影响。这三个目标共同检验了存在互惠和增强关系的总体假设在与星形胶质细胞对谷氨酸能张力的影响相关的酒精和星形胶质细胞激活之间细胞因子产生。这些创新的研究将洞悉星形胶质细胞在过渡到过渡中的作用酒精依赖，有关性别对酒精引起的神经免疫性变化的影响的新信息，以及我们对酒精滥用与神经免疫性失调之间关系的理解的转变。