Insula-BNST Circuit Regulation of AUD

Wake Forest University Health Sciences, Winston-Salem NC

Investigators

Abstract

PROJECT SUMMARY Alcohol use disorder (AUD) afflicts millions of individuals and their families. Current treatment options and clinical diagnostic tools are limited, necessitating more research on the progression from casual use to AUD in certain individuals. Identifying pre-AUD biomarkers, as is common practice with heart disease and diabetes, could impact millions of lives. However, addiction involves complex overlapping patterns that complicate pinpointing cause and effect, or quantifiable biomarkers, creating an inherent pitfall. Neuronal circuits are the basic functional units that encode behavior. A better understanding of the neurocircuits engaged prior to dependence could shift strategies away from reactive treatments, and towards preventative measures to mitigate risks of developing AUD. Stress is an individualized experience that is highly intertwined with alcohol use and AUD. Could basal stress activation of AUD-associated neurocircuitry reveal unique patterns that predict subsequent AUD-related behavior? The insular cortex (insula) is a key network hub for emotional regulation, salience detection, cognitive control, and sensory processing. Mounting clinical and preclinical evidence suggests activity patterns in the insula correlate with alcohol drinking behavior. We and others have characterized a particularly intriguing projection to the bed nucleus of the stria terminalis (BNST), a critical node for stress-related disorders such as anxiety, depression, and addiction. This circuit is basally quiescent, but highly responsive to stress, binge drinking, and negative affect in abstinence. A relationship between stress-induced insula-BNST activation and subsequent alcohol-related behavior has not been examined. We will test the central hypothesis that stress-induced neuroadaptations in the insula-BNST pathway are associated with future AUD-related behavior. We predict that a group of stress susceptible mice will exhibit high insula-BNST stress response and stress-induced neuroadaptations. These changes are expected to relate to aversion-resistant binge drinking and hyperkatifeia in abstinence, two key features of AUD. Validated mouse models of stress and binge ethanol drinking will be used to test our hypothesis. Aim 1 will use longitudinal strategies to examine the relationship between stress-activated insula-BNST circuitry and binge/aversive ethanol drinking. Aim 2 will identify neuroadaptations within the insula-BNST circuit after stress and alcohol exposure. Aim 3 will use RNA sequencing to compare the insula-BNST transcriptome after stress or binge alcohol exposure. Our goal is to identify overlapping transcriptional signatures in stress and AUD- related behavior. We will mechanistically validate the results with shRNA-mediated knockdown of the top molecular targets in the insula-BNST to determine their role in binge alcohol drinking. Understanding the signatures of AUD-related circuits can bridge the gap between molecular and genetic biomarkers, and broader activity-based digital biomarkers. This conceptually and technically innovative framework will inform improved diagnosis, intervention, and risk assessment before AUD manifests.