Translational Studies on Early-life Stress and Vulnerability to Alcohol Addiction

描述(由申请人提供)：本P01的主要目标是利用机构在人类、非人类灵长类动物和啮齿动物酒精研究方面的优势，进行旨在了解早期生活压力与酒精使用障碍易感性之间的复杂关系的转换研究。该项目将利用高效和 WFHS最近在NIAAA方案赠款支持下成立的成功的转化醇研究单位。这个研究单位将使用多学科方法来确定早期生活压力的持久行为和神经生物学后果，确定这些变化如何导致过度饮酒行为，并测试可能有效缓解与早期生活压力相关的成瘾脆弱性的新型干预策略。最重要的假设是，早期的生活压力会导致长期的行为改变，从而增加酒精成瘾的风险(重点是类似焦虑的行为)。还假设这些行为改变是由 部分是由于伏隔核多巴胺信号转导和谷氨酸受体功能及可塑性的失调。这些假设的方方面面将在有和没有早期生活压力史的人类受试者中进行评估，并使用已建立的早期生活压力的非人类灵长类动物和啮齿动物模型进行评估。P01将采用中心式结构，包括高度集成的啮齿动物、非人类灵长类动物和人类项目。行政核心将提供确保研究成功所需的基础设施和支助。该核心还将通过试点项目计划积极推动新的转化酒研究，并创建与P01的科学目标相关的新的转化性研究、培训和推广活动。一个主要的重点将是促进跨项目的科学整合，以最大限度地提高从替补发现到酒精成瘾的新治疗策略的可能性。

DESCRIPTION (provided by applicant): The major goal of this P01 is to leverage institutional strengths in human, non-human primate, and rodent alcohol research to conduct translational studies directed at understanding the complex relationships between early life stress and vulnerability to alcohol use disorders. This project will take advantage of a highly productive and successful translational alcohol research unit at WFHS that was recently established with NIAAA programmatic grant support. This research unit will employ multidisciplinary approaches to identify enduring behavioral and neurobiological consequences of early life stress, determine how these alterations contribute to excessive alcohol drinking behaviors, and test novel interventional strategies that may be effective at alleviating addiction vulnerability associated with early life stress. The overarching hypothesis is that early life stress results in long lastin behavioral alterations that contribute to an increased risk of alcohol addiction (with a focus on anxiety-like behaviors). It is also hypothesized that these behavioral alterations are mediated, in part, by dysregulatlon of dopamine signaling and glutamate receptor function and plasticity in the nucleus accumbens. Aspects of these hypotheses will be evaluated in human subjects with and without a history of early life stress and with well-established non-human primate and rodent models of early life stress. This P01 will employ a Center-like structure that will include highly integrated rodent, non-human primate, and human projects. An administrative core will provide the infrastructure and support needed to ensure the success of the research. This core will also actively promote new translational alcohol research through a pilot project program and create new translational research training and outreach activities related to the scientific goals f the P01. A major emphasis will be to promote scientific integration across projects to maximize the likelihood of proceeding from benchside discovery to novel treatment strategies for alcohol addiction.