Individual differences in cortical-stratal pathway utilization regulating flexibility

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Project Summary Addiction is a multifaceted, chronic neurobiological disorder occurring in only 15-30% of individuals who experiment with drugs of abuse. This individual variability suggests neurobiological differences present prior to any drug exposure, resulting in phenotypic behavioral differences across species. In rats, addiction-resistant “goal-trackers” (GT) flexibly adjust behavior when an outcome is devalued, independent of extent of training. Addiction-vulnerable “sign-trackers” (ST) fail to adjust their behavior and persistently show increased responding to learned cues despite outcome devaluation. I recently found this inflexibility in ST rats is only evident after limited training, as they become behaviorally flexible, similar to GT rats, after extended training. These transient behavioral differences suggest dissociable neurobiological mechanisms between phenotypes and across training. The long-term goal of this project is to understand the neurobiological differences underlying behavioral differences in addiction vulnerability phenotypes, and how these behavioral and neural differences change with training. I recently found communication between the anterior insular cortex (aIC) to nucleus accumbens core (NAcC) is necessary for outcome devaluation, specifically in GT rats, but not in ST rats. The aim of the current proposal is to examine how activation, excitability, and synaptic plasticity of the aICNAcC pathway mediates tracking- and experience-dependent behavioral flexibility. I hypothesize increased utilization of the aICNAcC pathway in GT rats compared to ST rats that regulates behavioral flexibility across training. In Aim 1, I will use pathway-specific chemogenetics to test the necessity and sufficiency of the aICNAcC pathway in outcome devaluation across training in GT and ST rats. In Aim 2, I will use ex vivo electrophysiological recordings in combination with pathway tracing and optogenetics to determine excitability and synaptic differences within the aICNAcC pathway between GT and ST rats after outcome devaluation. In Aim 3, I will use in vivo electrophysiological recordings in combination with optogenetics to measure real-time activity of the aICNAcC pathway in GT and ST during outcome devaluation. Investigating how the aICNAcC pathway mediates tracking- and experience-dependent differences in behavioral flexibility is necessary to further our understanding of neurobiological mechanisms that predispose individuals to addiction vulnerability prior to drug experience. The proposed experiments will advance my use of electrophysiological techniques and analysis of complex datasets. This application draws on the strong addiction expertise of faculty at University of Maryland School of Medicine to foster successful completion of the proposed training plan. Together, my proposed aims along with the strong mentorship and collaborative nature of my department ensures successful development as an independent scientist.