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

• 批准号: 10089613
• 负责人: Simon Alexander Marshall
• 金额: $ 36.65万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 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/10089613
• 关键词: 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; Brain Injuries; Cells; Consummatory Behavior; Consumption; Data; 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; 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; Time; 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; promoter; receptor expression; response; sex; social; socioeconomics

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加强关系的总体假设 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。