Sex differences in nucleus accumbens core circuitry engaged by binge-like ethanol drinking

Growing parity in Alcohol Use Disorder (AUD) diagnoses in men and women necessitates consideration of sex as a biological variable. In humans and rodents, the nucleus accumbens core (NAcc) regulates alcohol binge drinking, a risk factor for developing AUD. We labeled NAcc inputs with a viral retrograde tracer and quantified whole-brain c-Fos to determine the regions and NAcc inputs differentially engaged in male and female mice during binge-like ethanol drinking. We found that binge-like ethanol drinking females had 129 brain areas with greater c-Fos than males. Moreover, ethanol engaged more NAcc inputs in binge-like ethanol drinking females (as compared with males), including GABAergic and glutamatergic inputs. Relative to water controls, ethanol increased network modularity and decreased connectivity in both sexes and did so more dramatically in males. These results demonstrate that early-stage binge-like ethanol drinking engages brain regions and NAcc-inputs and alters network dynamics in a sex-specific manner.