Thalamostriatal Circuitry in Opioid Seeking

SUMMARY/ABSTRACT Reward-associated cues are unlikely to provoke reward seeking when that behavior is inappropriate, yet cues elicit opioid seeking in patients with opioid use disorder (OUD) when that behavior is unproductive or maladaptive. There is little understanding of how brain systems that can normally suppress unproductive reward seeking are modified by opioid use and causally contribute to opioid seeking. This is in part due to technical feasibility, as measuring adaptations in single neurons across the onset, maintenance, and relapse phases of opioid use is challenging. Here, I overcome this issue using a novel assay developed in my lab, wherein I longitudinally track activity in precisely defined neurons throughout heroin self-administration, extinction, and reinstatement using two-photon calcium imaging in head-restrained mice. We test the overarching hypothesis that a thalamostriatal subcircuit is inhibited by opioid use and by the presentation of stimuli that initiate opioid- seeking behaviors. In support of this hypothesis, my preliminary data suggest that posterior paraventricular thalamic neurons that project to the nucleus accumbens (pPVT NAc) become hypoactive and hypoexcitable as a result of repeated heroin use and display rapid reductions in activity during cue- and drug-induced reinstatement of heroin seeking. Furthermore, I show that optogenetically mimicking this inhibition during extinction initiates heroin seeking. To test my specific hypotheses, in Aim 1, I will longitudinally track the activity dynamics of single pPVT NAc neurons and neuronal ensembles throughout heroin self-administration, extinction, and reinstatement. In Aim 2, I will evaluate the long-lasting intrinsic and synaptic adaptations among pPVT NAc neurons at multiple timepoints following heroin self-administration. In Aim 3, I will determine the function of pPVT NAc neuronal activity for the suppression of heroin seeking during extinction, and expression of heroin seeking during reinstatement. Overall, this project will identify how a brain circuit that inhibits reward seeking in inappropriate conditions is modified by opioid use and causally influences opioid-seeking behavior.