Repeated Binge Drinking and the Genetic Regulation of Corticostriatal Synchrony

项目总结/文摘

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.