Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence

内侧前额叶皮质胶质生成和酒精依赖

• 批准号: 9121372
• 负责人: Chitra D Mandyam
• 金额: $ 25.03万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121372
• 关键词: Abstinence; Acute; Address; Adult; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; American; Animal Model; Animals; Behavior; Behavioral; Biochemical; Birth; Brain; Brain Mass; Brain region; Brain-Derived Neurotrophic Factor; CSPG4 gene; Cell Cycle Kinetics; Cell Proliferation; Cells; Cerebrovascular system; Chronic; Clinical Data; Cognition; Complex; Data; Dependence; Development; Diagnostic; Disease; Emotional; Ethnic Origin; Exercise; Future; Gender; Glial Fibrillary Acidic Protein; Heavy Drinking; Impaired cognition; Impairment; Individual; Injury; Intervention; Laboratories; Learning; Measures; Medial; Mediating; Memory; Modeling; Molecular; Morbidity - disease rate; Nerve Degeneration; Neurobiology; Neuroglia; Neuronal Plasticity; Pharmaceutical Preparations; Phenotype; Physical activity; Play; Predisposition; Prefrontal Cortex; Production; Psychopathology; Publishing; Race; Rattus; Regulation; Relapse; Research; Rewards; Rodent; Rodent Model; Role; Running; Self Administration; Self-Administered; Signal Transduction; Societies; Staging; Stem cells; Structure; Syndrome; System; Techniques; Testing; Withdrawal; addiction; alcohol effect; alcohol relapse; alcohol seeking behavior; alcohol use disorder; alcoholism therapy; behavior measurement; cognitive function; cognitive performance; drinking; economic cost; gliogenesis; innovation; interest; meetings; mortality; neocortical; neurotoxicity; non-drug; problem drinker; progenitor; protective effect; reinforcer; relating to nervous system; self-renewal; vapor

DESCRIPTION (provided by applicant): Alcohol use disorders, generally known as alcoholism, have taken emotional and financial tolls on American society, cutting across ages, races, ethnicities, and genders, with over 17 million Americans meeting the diagnostic criteria for alcohol abuse or dependence. Clinical data demonstrate alterations in brain structure and function in chronic alcoholics, injuries that may promote the individual s decline to meeting diagnostic criteria for alcohol dependence. Alcohol dependence is characterized by cycles of repeated high alcohol intake and negative emotional consequences of withdrawal that contribute to excessive drinking and susceptibility to relapse. There is a high likelihood that alcohol-dependent individuals will relapse to drinking even after long periods of abstinence, making treatment options challenging. One promising approach for the treatment of relapse to drinking is the identification of mechanisms that contribute to alcohol-induced reductions in brain mass and neurodegeneration. Recent evidence demonstrates that alcohol-induced neurodegeneration is affected by the decreased production of neural and glial progenitors in the adult brain. In the proposed studies, our research will specifically focus on alcohol s effects on the birth and survival of progenitors (glial stem cells and gliogenesis) in the medial prefrontal cortex (mPFC), a brain region implicated in the acute reinforcing effects of alcohol and relapse to alcohol-seeking behavior. Preliminary evidence from our laboratory demonstrated that excessive drinking in a rodent model of alcohol vapor-induced dependence decreased the proliferation and survival of adult-generated mPFC progenitors. Such regulation was not observed in nondependent alcohol self-administering rats, suggesting that the mPFC gliogenic niche is more vulnerable to dysregulation of the homeostatic system during dependence. These results raise a number of fundamental questions about the neuroplastic changes that contribute to alcohol dependence and the neuroplastic mechanisms that underlie the relapse stage of alcoholism. Therefore, this proposal will identify whether reduced gliogenesis in the mPFC could be a vulnerability factor for alcohol dependence and relapse. Animal models of excessive drinking during vapor-induced alcohol dependence and nondependent drinking will be used to (1) determine the cellular mechanisms underlying reduced mPFC plasticity during alcohol dependence (Specific Aim 1), (2) determine impairments in memory and cognitive function dependent on the mPFC during alcohol dependence (Specific Aim 2), and (3) demonstrate a causal relationship between newly born glial progenitors and relapse to alcohol seeking (Specific Aim 3). Immunohistochemical, biochemical, neuroanatomical, and behavioral measures will be used to determine the functional relationships between neocortical gliogenesis and alcohol dependence. The proposed aims will reveal new vulnerability markers for alcohol dependence and impart significant information about targets for medication development.

描述（由申请人提供）：酒精使用障碍（通常称为酒精中毒）给美国社会带来了情感和经济损失，跨越年龄、种族、民族和性别，超过 1700 万美国人符合酒精滥用或依赖的诊断标准。临床数据表明，慢性酗酒者的大脑结构和功能发生了变化，这些损伤可能会导致个体无法满足酒精依赖的诊断标准。酒精依赖的特点是反复大量饮酒和戒酒带来的负面情绪后果的循环，导致过度饮酒和容易复发。即使长期戒酒，酒精依赖者也很有可能重新酗酒，这使得治疗选择具有挑战性。治疗酗酒的一种有前途的方法是确定导致酒精引起的脑质量减少和神经退行性变的机制。最近的证据表明，酒精引起的神经变性受到成人大脑中神经和神经胶质祖细胞生成减少的影响。在拟议的研究中，我们的研究将特别关注酒精对内侧前额皮质（mPFC）祖细胞（神经胶质干细胞和胶质细胞生成）的出生和存活的影响，mPFC是一个与酒精的急性强化作用和酗酒行为复发有关的大脑区域。我们实验室的初步证据表明，在酒精蒸气引起的依赖的啮齿动物模型中过度饮酒会降低成年 mPFC 祖细胞的增殖和存活率。在非依赖性酒精自我给药大鼠中没有观察到这种调节，这表明 mPFC 神经胶质细胞生态位在依赖性期间更容易受到稳态系统失调的影响。这些结果提出了一些关于导致酒精依赖的神经可塑性变化以及酒精中毒复发阶段的神经可塑性机制的基本问题。因此，该提案将确定 mPFC 中胶质生成的减少是否可能是酒精依赖和复发的脆弱因素。蒸汽诱导的酒精依赖和非依赖饮酒期间过量饮酒的动物模型将用于（1）确定酒精依赖期间 mPFC 可塑性降低的细胞机制（具体目标 1），（2）确定酒精依赖期间依赖于 mPFC 的记忆和认知功能损伤（具体目标 2），以及（3）证明新生神经胶质祖细胞与酒精寻求复发之间的因果关系 （具体目标 3）。免疫组织化学、生物化学、神经解剖学和行为测量将用于确定新皮质胶质生成和酒精依赖之间的功能关系。拟议的目标将揭示酒精依赖的新脆弱性标记，并提供有关药物开发目标的重要信息。