Identifying a role for the mu-opioid receptor in the paraventricular nucleus of the thalamus in the development of stress related phenotypes

Project Summary/Abstract Stress and stressful environments often lead to maladaptive behaviors that can increase vulnerability to substance use disorders. The paraventricular nucleus of the thalamus (PVT) has been implicated in both stress and drug reward with a population of mu-opioid receptor-expressing neurons within the PVT (PVT- MOR+ neurons) potentially important for the maladaptive behaviors associated with stress. Individuals’ response to stress varies with some showing resilience, while others show susceptibility and are prone to the detrimental effects. While the relationship between stress and substance use disorders is well documented, there exists a significant gap in knowledge regarding the role of individual differences in stress susceptibility in mediating opioid reward. Furthermore, the neural pathways and cell types mediating the development of resilience or susceptibility phenotypes is unknown. The overall goals of this proposal are to A) determine how susceptible and resilient phenotypes influence subsequent opioid-taking and B) if a population of mu-opioid receptor (MOR) positive neurons in the PVT are necessary for the development of stress phenotypes. Our hypothesis is a susceptibility phenotype following social defeat stress will result in increases in opioid intake. We further hypothesize that activation of PVT-MOR containing neurons is necessary for establishing susceptibility following chronic social stress. Aim 1 will investigate how chronic stress response phenotypes influence opioid self-administration. Aim 2 will examine the role of PVT-MOR+ neurons in the development of stress phenotypes using chemogenomic tools to manipulate PVT-MOR+ neurons during chronic social defeat stress. Successful completion of these aims will establish if stress responsive subtypes differentially influence opioid reinforcement and will clarify the role of PVT-MOR+ neurons in behavioral responses to chronic social stress. Through this fellowship, Ms. Tyner will accomplish the defined Training Goals, including 1) technical training and mastery of neural circuit manipulation and viral imaging techniques, 2) expertise in the neurobiology of stress, 3) refined written and oral scientific communication, and 4) professional development towards a career in academic research. This fellowship will also facilitate progress towards achieving her current and future research goals to enable success as an independent researcher.