The Anterior Insular Cortex Inputs to the Dorsolateral Striatum Govern Binge-Like Alcohol Intake

Abstract

Binge alcohol consumption, defined as consuming four to five or more drinks in about two hours, represents a large proportion of the deaths and economic costs associated with problematic alcohol use. The primary goal of the experiments presented in this dissertation is to uncover how binge drinking alcohol alters synaptic function, and if these changes maintain and perpetuate future binge consumption. The anterior insular cortex (AIC) and dorsolateral striatum (DLS) are brain regions both heavily implicated in alcohol use. In male mice, we found that binge drinking alcohol produced glutamatergic synaptic adaptations selective to AIC neurons that project to the DLS. Photoexciting AIC→DLS circuitry during binge drinking decreased future alcohol, but not water consumption and altered alcohol drinking mechanics. Further, using machine learning approaches we showed that drinking mechanics alone from a single drinking session predicted alcohol-related circuit changes. Additionally, we aimed to determine why female mice displayed different alcohol-induced neuroadaptations after binge alcohol consumption. We showed that female mice display different behaviors in-between binge drinking sessions that influence the amount of alcohol they drink when they binge. For male and female mice that drink similar amounts of alcohol, the mechanics in which they achieved those intakes also differed by sex. Further, we used in-vivo calcium imaging in AIC terminals as a proxy for AIC neurotransmission into the DLS of awake, behaving, and binge drinking mice. We found sex- and time-dependent changes in AIC activity for both water and alcohol groups that also showed strong lateralization effects between AIC inputs that project to the left DLS versus the right DLS. Together, these findings suggest that alcohol-mediated changes in AIC inputs govern behavioral sequences that establish and maintain binge drinking in a sex- and time-dependent fashion and these alterations may serve as circuit-based biomarkers for the development of alcohol use disorder.