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

Maddern, X.; Pearl, A.; Tan, Q.; Dempsey, H.; Ursich, L.; Huckstep, K.; Richards, B.; Anversa, R.; Campbell, E.; Lawrence, A.; Brown, R.; Walker, L.

doi:10.64898/2026.02.10.705193

bioRxiv · 10.64898/2026.02.10.705193

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

Maddern, X.·Pearl, A.·Tan, Q.·Dempsey, H.·Ursich, L.·Huckstep, K.·Richards, B.·Anversa, R.·Campbell, E.·Lawrence, A.·Brown, R.·Walker, L.

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Abstract

BackgroundRates of binge drinking have converged significantly between the sexes over recent decades, driven by increased rates of alcohol misuse in women. However, understanding of fundamental circuitry and neurobiology driving alcohol use in females, or how this may differ from male subjects remains underexplored. MethodsWe quantified c-Fos expression across 40 brain regions in alcohol naive, alcohol anticipating and binge drinking male and female mice. In vivo fiber photometry examined sex differences in basolateral amygdala (BLA) activity changes to alcohol intake. Chemogenetic BLA inhibition investigated a functional role in binge drinking. We then assessed sex differences in BLA efferent projection activation following binge drinking. Finally, we functionally interrogated the BLA to nucleus accumbens core (AcbC) projection in binge drinking. ResultsBinge drinking reduced network modularity (number of communities with similar activation patterns) in both sexes relative to alcohol naive and anticipating same-sex counterparts. Female binge drinking mice had increased BLA c-Fos expression compared to female naive and male binge drinking counterparts. In vivo fiber photometry revealed greater and more prolonged BLA responsivity at the onset of alcohol intake in females. Global BLA inhibition reduced reward intake in both sexes. However, the BLA to AcbC projection was preferentially activated in female binge drinking mice, and inhibition of this pathway reduced binge alcohol intake exclusively in females. ConclusionsWe identified sex differences in the neural circuits engaged in binge drinking, highlighting the BLA to 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.

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Maddern, X., Pearl, A., Tan, Q., Dempsey, H., Ursich, L., Huckstep, K., Richards, B., Anversa, R., Campbell, E., Lawrence, A., Brown, R., Walker, L.. 2026-02-12. Sex differences in neural circuits driving binge drinking: A female-specific role for an amygdalo-striatal pathway. https://doi.org/10.64898/2026.02.10.705193

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