The neurobiological mechanisms behind compulsive (dependent) alcohol intake involve a progressive dysregulation of brain circuits that subserve reward, stress and motivation. While histone modifications were historically considered static, mounting evidence is revealing an unexpected degree of plasticity and suggests that long-lasting changes in gene expression due to altered histone regulation may, in principle, be reversible. In post-mitotic neurons, histone modifications are emerging as potential players in processes like learning and memory and the effects of drugs of abuse. Thus, the hypothesis under test in the present proposal is that long-lasting post-translational histone modifications in brain regions that subserve reward, stress and motivation are key to the neuroadaptations that underlie excessive alcohol consumption. To test this hypothesis, the present proposal will conduct a genome-wide investigation of changes of selected activation and repression histone marks induced by alcohol dependence in 1) chronic intermittent exposure (CIE), a paradigm of dependence-associated increased drinking that is proposed throughout the INIA consortium;and 2) mice with manipulation of the level of the G protein beta 1 subunit (0(31), which was identified by the INIA consortium as a regulator of alcohol drinking that can directly regulate chromatin dynamics. We will then expand the investigation of histone modifications at the differentially regulated genes identified to additional histone marks associated with chromatin states to define the repertoire of histone modifications that characterizes excessive alcohol intake. Lastly, we will validate the functional significance of the patterns of histone modifications observed at the differentially regulated genes with biochemical, morphological and behavioral strategies. For the mapping and quantitation of histone modifications across the genome and at specific genes, we will use chromatin immunoprecipitation coupled with tiling arrays (ChlP-Chip) or quantitative real time PCR (ChlP-PCR), respectively. Data will be integrated with gene expression, behavioral and pharmacological data generated across the INIA consortium. The results of this project will contribute to lay the foundation for an integrated systems biology analysis of the neurobiology of excessive alcohol consumption
Converging lines of evidence suggest a potential role for chromatin regulation in excessive alcohol consumption and alcoholism. The present project will explore genome-wide patterns of post-translational histone modifications in animal models of excessive drinking that will be investigated across the INIA consortium with other approaches. The dataset generated, in concert with the results of other INIA studies, will foster the identification of new therapeutic targets for the prevention and treatment of alcohol abuse,
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