The impact of adolescent stress on neural circuits underlying punishment resistant reward seeking

PROJECT SUMMARY/ABSTRACT Adolescence is a critical period of development characterized by rapid physiological and behavioral changes. These widespread changes mark adolescence as a period of particular vulnerability to adverse experiences, such as chronic stress. Indeed, chronic stress during adolescence is widely recognized as a risk factor for the development of multiple psychiatric disorders, including addiction. With self-reporting of chronic stress on the rise in adolescents—especially in the wake of the COVID-19 pandemic—there is an urgent need to understand the effects of adolescent chronic stress on the neural mechanisms underlying behaviors linked to addiction. Here, I examine one such behavior, punishment-resistant reward seeking, in which animals maintain their pursuit of reward in the face of negative consequences. This proposal aims to establish that a projection from the central amygdala (CeA) to the lateral substantia nigra (SNL) is a key interface between stress and punishment-resistant reward-seeking. I hypothesize that chronic stress in adolescence leads to enduring hyperexcitability of SNL-projecting CeA neurons, causing increased inhibition of SNL GABA neurons and a net disinhibition of SNL dopamine neurons. I hypothesize that this disinhibition of SNL dopamine neurons increases punishment-resistant reward seeking. I will test this hypothesis using operant behavior, in vivo fiber photometry, and chemogenetics (Aim 1) alongside in vitro patch-clamp electrophysiology (Aim 2). I will characterize long-term adaptations in the CeAàSNL pathway after adolescent chronic stress along with the links between those neural adaptations and changes in the propensity for punishment-resistant reward-seeking. My proposal will aid in the identification of the biological and behavioral causes of addiction, in accordance with NIDA’s goals. Over the course of this fellowship, I will receive training in teaching, communication, programming, and grant writing. I will further my knowledge of drug abuse and addiction through coursework, practice, and conference participation. Ultimately, this fellowship will support my goal of becoming an independent investigator studying how perturbations in subcortical circuits during development lead to addiction and other psychiatric disorders.