Characterization of Insula to BNST Circuit Adaptations Following Chronic Ethanol Intake

Abstract

The insular cortex (IC) integrates sensory and interoceptive cues to inform downstream circuitry executing adaptive behavioral responses. The IC communicates with areas involved canonically in stress and motivation. IC projections govern stress and ethanol recruitment of bed nucleus of the stria terminalis (BNST) activity necessary for the emergence of negative affective behaviors during alcohol abstinence. Here, we assess the impact of the chronic drinking forced abstinence (CDFA) volitional home cage ethanol intake paradigm on synaptic and excitable properties of IC neurons that project to the BNST (IC→BNST). Using whole cell patch clamp electrophysiology, we investigated IC→BNST circuitry 24hrs or 2 weeks following forced abstinence (FA) in female C57BL6/J mice. We find that IC→BNST cells are transiently more excitable following acute ethanol withdrawal. In contrast, in vivo ethanol exposure via i.p injection, ex vivo via ethanol wash and acute FA from a natural reward (sucrose) all failed to alter excitability. In situ hybridization studies revealed that at 24hrs post FA BK channel mRNA expression is reduced in IC. Further, pharmacological inhibition of BK channels mimicked the 24hr FA phenotype, while BK activation was able to decrease AP firing in control and 24hr FA subjects. All together these data suggest a novel mechanism of homeostatic plasticity that occurs in the IC-BNST circuitry following chronic drinking.