Description:

Xunhui Wu PhD, PhD Candidate
Parker Lab
Department of Neuroscience

Abstract:

Environmental stimuli associated with drug use can become powerful triggers for drug-seeking behavior. Specifically, opioid-induced dopamine release is thought to reinforce the environmental stimuli and actions associated with opioid administration by modifying the neural circuits underlying motivated behavior—a process that is not fully understood. One of the involved circuits is the dorsal striatum, which has long been recognized as an important hub for reinforcement learning and action selection. The dorsal striatum is densely innervated by midbrain dopamine neurons and itself expresses the receptor for opioids (μORs), which are specifically enriched in the striosomal compartment. μOR-expressing, striosomal neurons preferentially project back to the midbrain dopamine neurons, while neighboring μOR-lacking neurons in the matrix have more canonical direct and indirect basal ganglia pathway projections. Because μORs are inhibitory, opioids are predicted to inhibit striatal striosomal neurons. This in turn is predicted to disinhibit striatal matrix and midbrain dopamine neurons. This milieu, dopamine release and disinhibited striatal activity, could be a recipe for pathological drug-seeking behavior. To test these ideas, we have integrated a dual-color, somatic calcium imaging with two-photon microscopes to simultaneously record activity in μOR-expressing and μOR-lacking dorsal striatal neurons in mice following acute administration of morphine. We have also developed viral genetic approaches to determine whether μOR expression in different striatal subregions is necessary and sufficient for morphine-induced dopamine release and/or conditioned place preference. By characterizing the cell-type-specific dynamics of an important, habit-associated brain region in opioid reinforcement, our experiments contribute to our basic knowledge of the neural substrates underlying the transition to compulsive opioid use.