Tuesday, May 27, 2025
5/27/2025
Modeling age-specific computational strategies during reward seeking - PROJECT SUMMARY The neuronal circuitry underlying motivational processes in adolescent models is understudied but clinically relevant because disorders such as depression, schizophrenia, and substance use disorder, which are marked by alterations in motivation, emerge during adolescence. The frontal cortex and striatum are critical targets because they are amongst the last regions to mature. My current work investigated how orbitofrontal cortex (OFC)-dorsomedial (DMS) circuits control response inhibition in adolescent and adult rats, and the impact of adolescent alcohol exposure on these networks. I found that adolescent alcohol exposure is associated with changes in OFC and DMS response to conditioned stimuli and rats' ability to inhibit a response in adulthood. In alcohol-naive animals, adolescents and adults differed in response to both reward, and actions preceding rewards in both the OFC and DMS. In a separate study, I recorded from dopamine neurons and observed that adolescents exhibited a larger phasic response to reward in a stimulus-driven task, while adults exhibit a larger response when reward is acquired during a goal-driven task. Collectively, these data suggest adolescent alcohol exposure promotes lasting changes in OFC-DMS circuits, and that adolescents and adults employ different computational strategies during reward-seeking, likely due to age-specific activity in cortical-striatal circuits. The proposed projects use a combination of in vivo electrophysiology recordings, computational modeling and chemogenetics to test the hypotheses that (1) developmental maturation is characterized by an enhanced ability to employ goal-directed control of behavior and (2) adolescent alcohol exposure causes pathology in neural circuits required for goal-directed control, thereby leading to risk of addiction-related behaviors. I will simultaneously record single units and local field potentials in the OFC and DMS in adolescent and adult rats performing an operant conditioning task (Aim 1). Next, I will integrate experimental and computational approaches to model neural strategies underlying motivated behavior in adolescents and adults (Aim 2). During the independent phase, I will use chemogenetics to test the model predictions and determine causality between behavior and physiology (Aim 3), and determine how engagement of different computational strategies is impacted by adolescent alcohol exposure and associated with addiction vulnerability (Aim 4). These translational results will enhance our mechanistic and computational understanding of adolescent brain function which is fundamental for understanding the etiology and pathophysiology of disorders with an adolescent onset, such as addiction.
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