Mechanisms of prelimbic somatostatin interneurons in opioid seeking behaviors - Opioid use disorder is a chronic relapsing condition marked by compulsive opioid seeking, impaired decision- making, and persistent neurophysiological disruptions, yet the cortical circuit mechanisms driving these behaviors remain unknown. Although addiction research has historically focused on mesolimbic dopamine pathways, growing evidence indicates that the prelimbic cortex exerts essential top-down control over reward valence evaluation, cue-guided behaviors, and impulse control. Within this region, somatostatin-expressing interneurons (SST-INs) are positioned to regulate dendritic integration, excitatory output, and exhibit learning- related plasticity, and recent findings demonstrate that opioids strongly modulate their excitability and synaptic transmission with exposure to opioids. The proposed work seeks to determine how SST-INs become engaged, altered, and potentially dysregulated during morphine self-administration, with the long-term objective of identifying inhibitory microcircuit mechanisms that contribute to compulsive opioid seeking and may be leveraged to restore prefrontal function in opioid use disorder. This project integrates intravenous operant morphine self-administration with in vivo calcium imaging, precise chemogenetic manipulation, and ex vivo whole-cell electrophysiology to dissect how SST-INs encode maladaptive reward learning and seeking. Aim 1 will define the evolution of SST-IN activity across acquisition and expression of morphine seeking, resolving how these neurons respond to cue presentation, approach behavior, lever pressing, and drug infusion across days of training and testing. Aim 2 will test the contribution of SST-INs to drug seeking by suppressing their activity with chemogenetics during testing allowing direct assessment of whether SST-INs promote or constrain morphine-seeking actions. Aim 3 will identify the intrinsic and synaptic plasticity mechanisms that emerge following morphine self-administration by measuring intrinsic excitability, excitatory/inhibitory balance, and presynaptic function in SST-INs from self-administration trained animals. By linking behavior, physiological plasticity, and real-time circuit dynamics, this work will clarify how opioids reshape inhibitory control in prefrontal cortex and define the mechanisms through which SST-IN dysfunction contributes to maladaptive reward processing. The fellowship will be supported in an environment with established expertise in operant drug self-administration, neural circuit dissection, and physiology recordings. Together, this project aims to advance understanding of cortical inhibitory dysfunction in opioid addiction and inform strategies designed to restore prefrontal circuit balance, improve inhibitory control, and reduce opioid-seeking behavior.
