Sex-dependent, lateralized engagement of anterior insular cortex inputs to the dorsolateral striatum in binge alcohol drinking.

How does alcohol consumption alter synaptic transmission across time, and do these alcohol-induced neuroadaptations occur similarly in both male and female mice? Previously we identified that anterior insular cortex (AIC) projections to the dorsolateral striatum (DLS) are uniquely sensitive to alcohol-induced neuroadaptations in male, but not female mice, and play a role in governing binge alcohol consumption in male mice (Haggerty et al., 2022). Here, by using high-resolution behavior data paired with in-vivo fiber photometry, we show how similar levels of alcohol intake are achieved via different behavioral strategies across sexes, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Furthermore, we show how presynaptic calcium activity recorded from AIC synaptic inputs in the DLS across 3 weeks of water consumption followed by 3 weeks of binge alcohol consumption changes across, fluid, time, sex, and brain circuit lateralization. By time-locking presynaptic calcium activity from AIC inputs to the DLS to peri-initiation of drinking events we also show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption. These findings suggest a fluid-, sex-, and lateralization-dependent role for the engagement of AIC inputs into the DLS that encode binge alcohol consumption behaviors and further contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS.