SEX-DEPENDENT 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? Previous work shows 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. Here, by using high-resolution behavior data paired with in-vivo fiber photometry, we show how similar levels of alcohol intake are achieved by different behavioral strategies across sex, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Further, 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 change 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 bouts we show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption and AIC inputs into the right DLS in males, but not females. Finally, we demonstrate how binge alcohol intake decreases AIC input engagement as alcohol intake progresses in both the left and right inputs into the DLS for males. 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 contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS.