Repeated Binge Drinking and the Genetic Regulation of Corticostriatal Synchrony

项目摘要/摘要 家长资助的长期目标--反复酗酒与皮质纹状体的基因调控 同步性，是识别基因网络(以及调节这些网络的关键基因)由重复招募 在被认为与酒精失控有关的大脑区域内过度饮酒 消耗-内侧前额叶皮质(MPFC)和腹侧纹状体(VSTR；即伏隔核)。 此外，这笔赠款的重点是确定反复过量饮酒的功能后果 饮酒--即过度饮酒后大脑功能如何变化，以及基因网络如何变化 都与这些大脑功能的变化有关。这项工作将导致更好地理解为什么以及如何进行 饮酒会导致上瘾，并将帮助我们制定预防和治疗过度饮酒的策略； 其中与NIAAA在了解酒精使用的神经生物学方面的使命直接相关 精神障碍(AUDS)。然而，最近出现的证据表明，过度饮酒是一种严重的风险 阿尔茨海默病(AD)及其相关痴呆(AD/ADRDS)的发病因素。给定 在这一领域，使用经过验证的AD/ADRD动物模型进行的临床前工作很少，我们的专业知识 评估过度饮酒的后果，我们完全有能力做出显著的 对关于过度饮酒和AD/ADRDS发展的新兴研究领域的贡献。这个 本补充剂申请中提出的研究旨在测试酗酒的假设 整个成年早期的消费将导致病理性tau(Ptau)的比率和程度的增加。 积累和认知能力下降，以及大脑中基因共表达网络的招募 调停这种互动。我们建议通过两个特定的目标(SA)来探索这一假设，这两个目标都是 使用与AD/ADRDS-P301S小鼠相关的经验证的牵张症小鼠模型。SA1：确定 Tau的神经病理指标与认知功能减退和饮酒的关系 P301S小鼠牵张症模型中的数量/模式。SA2：识别基因共表达网络和关键 调控tau病理和认知能力下降的“Hub”基因是酒精暴露的P301S小鼠特有的。 拟议研究的结果将有助于确定不同的数量和模式 整个青年时期的酗酒影响tau病理和相关认知的进展 拒绝。这项工作还将确定与酒精介导的改变有关的关键神经生物学基因网络 在tau病理和相关的认知功能衰退中。总之，从这项工作中获得的结果将提供 发展一门新的研究学科的关键初步数据和科学依据 酒精使用障碍对AD/ADRDS发展和恶化的影响

PROJECT SUMMARY/ABSTRACT The long-term goal of the parent grant, ‘Repeated Binge Drinking and the Genetic Regulation of Corticostriatal Synchrony’, is to identify gene networks (and key genes regulating these networks) recruited by repeated binge alcohol consumption within brain areas thought to be involved in loss of control over alcohol consumption - the medial Prefrontal Cortex (mPFC) and the ventral Striatum (vSTR; i.e. nucleus accumbens). Additionally, this grant focuses on identifying the functional consequences of repeated excessive alcohol consumption – that is, how brain function changes as a results of excessive drinking, and how gene networks are involved in these changes in brain function. This work will result in a better understanding of why and how alcohol use leads to addiction, and will help us develop strategies to prevent and treat excessive drinking; both of which are directly relevant to the mission of the NIAAA in understanding the neurobiology of alcohol use disorders (AUDs). However, recent evidence has emerged that excessive alcohol consumption is a critical risk factor for the development of Alzheimer’s disease (AD) and its related dementias (AD/ADRDs). Given the paucity of preclinical work in this area using validated animal models of AD/ADRDs, and our expertise in evaluating the consequences of excessive alcohol drinking, we are perfectly positioned to make significant contributions to the emerging field of study on excessive alcohol use and the development of AD/ADRDs. The studies proposed in this Supplement application were designed to test the hypothesis that binge alcohol consumption throughout early adulthood will lead to increases in the rate and extent of pathological tau (pTau) accumulation and cognitive decline, as well as the recruitment of gene co-expression networks in brain that mediate this interaction. We propose to explore this hypothesis through two Specific Aims (SAs), both of which use a validated mouse model of tauopathy relevant to AD/ADRDs - P301S mice. SA1: Determine the relationship between neuropathological measures of tau, cognitive decline, and alcohol drinking amount/patterns in the P301S mouse model of tauopathy. SA2: Identify gene co-expression networks and key ‘hub’ genes regulating tau pathology and cognitive decline that are unique to alcohol exposed P301S mice. The results of the proposed studies will help in identifying the extent to which different amounts and patterns of binge drinking throughout young adulthood impacts the progression of tau pathology and associated cognitive decline. This work will also identify key neurobiological gene networks involved in alcohol-mediated alterations in tau pathology and associated cognitive decline. Together, the results obtained from this work will provide critical preliminary data and scientific rationale for the development of a new research discipline evaluating the effects of alcohol use disorders on the development and exacerbation of AD/ADRDs.