Medial Prefrontal Cortical Gliogenesis and Alcohol Dependence

描述（由申请人提供）：酒精使用障碍，通常被称为酒精中毒，对美国社会造成了情感和经济上的损失，跨越了年龄、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。临床资料表明，慢性酒精成瘾者的大脑结构和功能发生改变，损伤可能会促使个体下降，无法达到酒精依赖的诊断标准。酒精依赖的特点是反复高酒精摄入的循环和戒断的负面情绪后果，导致过度饮酒和易感性复发。酒精依赖者即使在长时间戒酒后也很有可能再次酗酒，这使得治疗方案具有挑战性。一种很有希望的治疗酗酒复发的方法是确定酒精导致脑质量减少和神经变性的机制。最近的证据表明，酒精诱导的神经变性受到成人大脑中神经和胶质祖细胞产生减少的影响。在这些研究中，我们的研究将特别关注酒精对内侧前额叶皮层（mPFC）中祖细胞（胶质干细胞和胶质细胞生成）的出生和存活的影响，内侧前额叶皮层是一个涉及酒精急性强化效应和寻求酒精行为复发的大脑区域。我们实验室的初步证据表明，在酒精蒸汽诱导的依赖啮齿动物模型中，过量饮酒会降低成年产生的mPFC祖细胞的增殖和存活。在非依赖酒精自我给药的大鼠中没有观察到这种调节，这表明在依赖期间，mPFC胶质源性生态位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和酒精复发阶段的神经可塑性机制的基本问题。因此，本研究将确定mPFC中胶质细胞生成减少是否可能是酒精依赖和复发的易感因素。在蒸汽诱导的酒精依赖和非依赖型饮酒期间过度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（特异性目标1），(2)确定酒精依赖期间mPFC依赖的记忆和认知功能损伤（特异性目标2），以及(3)证明新生胶质祖细胞与酒精寻求复发之间的因果关系（特异性目标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形成与酒精依赖之间的功能关系。提出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。

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.