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

描述（由申请人提供）：本P01的主要目标是利用人类、非人灵长类动物和啮齿动物酒精研究的机构优势，进行旨在了解早期生活压力与酒精使用障碍易感性之间复杂关系的转化研究。该项目将利用一个高生产力和 在WFHS成功的翻译酒精研究单位，最近成立的NIAAA计划赠款支持。该研究单位将采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，确定这些改变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。总体假设是，早期生活压力导致长期的行为改变，导致酒精成瘾风险增加（重点是焦虑样行为）。还假设这些行为改变是通过 部分是由于中脑背核内多巴胺信号和谷氨酸受体功能及可塑性的失调。这些假设的各个方面将在具有和不具有早期生活应激史的人类受试者中以及在具有良好建立的非人灵长类动物和啮齿类动物早期生活应激模型中进行评价。P01将采用类似中心的结构，包括高度整合的啮齿动物、非人类灵长类动物和人类项目。一个行政核心将提供必要的基础设施和支持，以确保研究的成功。该核心还将通过试点项目计划积极促进新的转化酒精研究，并创建与P01科学目标相关的新的转化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临床发现到酒精成瘾新治疗策略的可能性。 公共卫生相关性：拟议的研究概述了一项多学科的转化研究计划，该计划将汇集人类，非人类灵长类动物和啮齿动物酒精研究人员，以解决有关将早期生活压力和酒精成瘾联系起来的神经生物学机制的复杂和未解决的问题。这些转化研究将 与早期环境压力相关的重要行为表型，它们与过量饮酒的关系，以及可能构成这些关系基础的特定神经生物学机制的新发现。该项目还将探索新的干预策略，可以减轻与早期生活压力相关的成瘾脆弱性增加。

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. PUBLIC HEALTH RELEVANCE: The proposed studies outline a multidisciplinary, translational research initiative that will bring together human, non-human primate, and rodent alcohol researchers to address complex and unresolved questions regarding the neurobiological mechanisms that link early life stress and alcohol addiction. These translational studies will shed new light on important behavioral phenotypes associated with early environmental stress, their association with excessive alcohol drinking, and specific neurobiological mechanisms that may underlie these relationships. This project will also explore novel interventional strategies that may mitigate the increased addiction vulnerability associated with early-life stress.