Meghan Elizabeth Gallo, Ph.D. - US grants

PROJECT SUMMARY Early life adversity (ELA) is associated with a significant increase in risk for substance use disorder. However, the mechanisms by which ELA increases the risk for substance use disorder are not well understood. Here, I will test hypotheses about how ELA shapes motivation for reward as a function of reward availability by altering the striatal dopamine system in a mouse model. In preliminary data, I demonstrate ELA increases ?behavioral opportunism?, exerting more effort on immediately available and more probable rewards, and less effort on more distant, less probable rewards, compared to controls. I hypothesize the ELA amplifies behavioral opportunism by altering both relatively static receptor expression and dynamic striatal dopamine signaling. In Aim 1, I will test the hypothesis that ELA-induced alterations in dopamine receptor D1 expression (traditionally associated with reward/benefit sensitivity) and D2 expression (traditionally associated with effort/cost sensitivity) are sufficient to alter cost-benefit trade off calculations to produce behavioral opportunism. Specifically, I will leverage a biologically informed computational model of behavior to assess the impact of striatal dopamine signaling on cost-benefit calculations. Next, I will test whether the model generalizes and can predict behavioral opportunism in a probabilistic bandit task, altering between rich and poor reward environments. Independent of relatively stagnant alterations in the dopamine receptors (Aim 1), I hypothesize that ELA steepens the dopamine ramp to dynamically produce behavioral opportunism (Aim 2). In Aim 2, I will build a dynamic model of an animal?s instantaneous perception of state value (how rewarding the environment is at a particular moment) to make predictions about behavior in discrete, within-trial behaviors (e.g. trial initiation, and reward retrieval). This model will be designed to recapitulate my preliminary data showing that ELA animals exhibit delays to initiate ?harder? trials, but then exhibit steeper increases in speed when reward is near or readily available. Based on prior work showing that dopamine tone tracks state value, I will use in vivo fiber photometry to measure real time dopamine release to test the hypothesis that striatal dopamine produces dynamic behavioral opportunism by encoding more dynamic changes in state value. Through the Research and Training Plan, the I will deepen my theoretical and conceptual knowledge of behavioral, cognitive and neural mechanisms underlying learning and behavior, while acquiring advanced systems neuroscience and quantitative techniques, including in-vivo fiber photometry, computational modeling and sophisticated behavioral analysis. The training acquired through this grant will allow the applicant to use an interdisciplinary approach when addressing how early life experience shapes motivation and decision-making. Overall, the proposed work will inform a rich literature regarding the mechanisms by which early life experiences lead to alterations in motivation and striatal dopamine. This work will provide insight into ELA vulnerabilities that could help explain why early life trauma increases the propensity for substance use disorder.