Sex differences in neural circuits driving binge-like drinking: a female-specific role for an amygdalo-striatal pathway

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Rates of binge drinking have converged significantly between the sexes over recent decades, driven by increased rates of alcohol misuse in women. However, understanding of the fundamental circuitry and neurobiology driving alcohol use in females, or how this may differ from male subjects remains underexplored. Here, we quantified c-Fos expression across 40 brain regions in alcohol naïve, alcohol anticipating and binge-like drinking male and female mice. The basolateral amygdala (BLA) was of particular interest given the robust sex differences in c-Fos expression, with female mice showing greater alcohol-associated expression. This was confirmed with in vivo calcium imaging revealing greater and more prolonged BLA responsivity at the onset of alcohol intake in female mice. To functionally test this, we used chemogenetic inhibition, however non-specific inhibition of the BLA broadly reduced alcohol and other reward intake in both sexes. Given the diversity of BLA efferent projections we assessed sex differences in c-Fos expression in BLA efferent projections following alcohol consumption drinking, identifying preferential activation of the BLA to nucleus accumbens core (AcbC) projection in female mice. Precision chemogenetic inhibition of the BLA→AcbC pathway reduced binge-like alcohol intake sex-specifically in females. Together, this study uncovers sex differences in the neural circuits engaged in binge-like drinking, highlighting the BLA→AcbC projection may in part underpin sex differences in alcohol misuse. This provides further evidence of distinct neurobiological drivers of alcohol-related behaviors between the sexes.