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Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward. However, the microglial molecular and cellular pathways associated with EtOH binge consumption remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>In this study, adult C57BL\/6J male and female mice were subjected daily to a gelatin\u2010based drinking\u2010in\u2010the\u2010dark voluntary EtOH consumption paradigm (3\u00a0h\/d for 4\u00a0months) to characterize EtOH consumption and withdrawal\u2010associated and anxiety\u2010like behaviors. Brain microglia were isolated at the end and analyzed for protein expression profile changes using unbiased mass spectrometry\u2010based proteomic analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both male and female mice consistently consumed binge quantities of EtOH daily, resulting in blood EtOH levels\u00a0&gt;\u00a080\u00a0mg\/dl measured at the end of the 3\u2010hour daily consumption period. Although female mice consumed a significantly greater amount of EtOH than male mice, EtOH withdrawal\u2010associated anxiety\u2010like behaviors measured by marble\u2010burying, light\u2010dark box, and elevated plus maze tests were predominantly observed in male mice. Proteomic analysis of microglia isolated from the brains of animals at the end of the 4\u2010month binge EtOH consumption identified 117 and 37 proteins that were significantly up\u2010 or downregulated in EtOH\u2010exposed male and female mice, respectively, compared to their pair\u2010fed controls. Protein expression profile\u2010based pathway analysis identified several cellular pathways that may underlie the sex\u2010specific and EtOH withdrawal\u2010associated behavioral abnormalities.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, our findings revealed sex\u2010specific changes in EtOH withdrawal\u2010associated behaviors and signaling pathways in the mouse brain microglia and may help advance our understanding of the molecular, cellular, and behavioral changes related to human binge EtOH consumption.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14420","type":"journal-article","created":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T05:39:59Z","timestamp":1596865199000},"page":"1791-1806","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Chronic Voluntary Binge Ethanol Consumption Causes Sex\u2010Specific Differences in Microglial Signaling Pathways and 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