Sex specificity of corticolimbic circuit activity and anxiety-like behavior after alcohol exposure

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Sex specificity of corticolimbic circuit activity and anxiety-like behavior after alcohol exposure Alcohol use disorder (AUD) is a complex clinical condition that is commonly associated with other psychiatric conditions like anxiety and depression. Despite significant differences in the prevalence and experience of AUD in men and women, few studies have examined the neurobiological mechanisms underlying sex-specific effects of alcohol on specific brain regions. The prelimbic prefrontal cortex (PrL) and central amygdala (CeA) have been implicated in both anxiety and alcohol dependence. Our previous work revealed sex-specific differences in PrL and CeA activity and anxiety-like behavior following chronic ethanol exposure. Alcohol is acutely anxiolytic, but prolonged exposure produces an anxiogenic phenotype, particularly in withdrawal. The impact of basal anxiety levels in sex-specific alcohol sensitivity in PrL and CeA and the role of PrL→CeA in sex differences in anxiety- like behavior following chronic alcohol exposure remains unknown and offers a potential target for improved understanding of AUD. Preclinical and emerging clinical evidence indicate that the neurosteroid allopregnanolone may be a potential therapeutic strategy for the treatment of AUDs via actions on GABAA receptor-mediated inhibitory control. As our previous work demonstrated sex-specific adaptations in inhibitory control in PrL and CeA, we will also investigate the impact of allopregnanolone on ethanol-induced dysregulation. We will employ an integrated molecular, cellular electrophysiological, and whole-animal imaging approach to rigorously examine sex differences in PrL, CeA, and Pr→CeA circuitry and any sex-specific effects in synaptic transmission, E/I balance, and network activity following chronic ethanol exposure and withdrawal. We will also assess the impact of allopregnanolone on any sex-specific changes following chronic ethanol exposure as a potential therapeutic strategy for the treatment of AUD. The results of these studies will provide important information on sex differences in the activity of PFC and CeA circuits and anxiety-like behavior and uncover the potential effects of a pharmacological approach to reverse specific circuit dysfunction following chronic ethanol exposure.