A Bridge Between Integration Stations: Insula’s Connection with the ventral Bed Nucleus of the Stria Terminalis

Abstract

Individuals suffering from substance use disorder often experience relapse events that are attributed to drug craving. Insular cortex (IC) function is implicated in processing drug-predictive cues and is thought to be a critical substrate for drug craving. Here, we uncover the functional connectivity of a novel projection from the IC to the ventral bed nucleus of the stria terminalis (vBNST), a portion of the extended amygdala shown to modulate dopaminergic activity within the ventral tegmental area, and investigate the role of this pathway in establishing reward-predictive cues. We hypothesized that these cues activate IC projections that synapse onto projection neurons within the vBNST, which then activate the mesolimbic dopamine pathway, resulting in the acquisition of associations between exteroceptive stimuli and rewards. In addition, due to the BNST’s role in ethanol self-administration combined with IC’s role in processing interoceptive cues associated with addictive substances, we predicted exposure to ethanol would affect the characteristics of vBNST-projecting IC neurons. Here we utilized both ex vivo slice electrophysiology and in vivo optogenetics to examine the functional connectivity and bidirectionally control the IC-vBNST projection in various reward-related behavioral paradigms. We also examined the effect of alcohol consumption on the IC-vBNST projection in acute and repeated ethanol exposure as well as in withdrawal. This work provides a potential mechanism by which the IC processes exteroceptive triggers that are predictive of reward.