Mesolimbic adaptations underlying altered reward sensitivity in neuropathic pain - PROJECT SUMMARY Chronic neuropathic pain (CNP) is characterized by emotional-affective symptoms, which afflict between 27- 75% of patients and are associated greater pain intensity, reduce compliance with pain management interventions and drive reduced quality of life in CPN patients. Despite this, there are no effective therapies for depression symptoms of chronic pain, and these symptoms do not respond to classical antidepressant therapies. Neuroimaging studies have shown blunted accumbal dopamine release in response to reward in chronic pain patients, prompting the hypothesis that a hypodopaminergic state underlies affective symptoms in chronic pain. However, direct evidence for the involvement of altered dopaminergic function in CNP is contradictory; and the precise mechanisms underlying the emergence of a hypodopaminergic state remain unknown, preventing the development of targeted therapies for its reversal. Our long-term goal is to inform novel pharmacological or neuromodulation therapies to treat affective symptoms of CNP. To this end, we must first understand whether altered function of dopamine neurons drives changes in reward-related behavior in CNP, as well as the cellular and circuit mechanisms underlying this altered function. To this end, we will first quantify changes in dopamine release in the nucleus accumbens core (NAcC) across the development of CNP. We will take advantage of novel optical approaches to longitudinally quantify changes in tonic and reward-evoked NAcC dopamine release in the same animals over the acute to chronic pain transition (Aim 1). We will then use patch-clamp electrophysiology with intersectional genetic labeling to record from NAcC-projecting dopamine neurons at acute- and chronic- timepoints following nerve injury to characterize the cellular mechanisms by which dopamine dysfunction is instantiated in CNP, which will ultimately be necessary to design therapies to reverse this dysfunction (Aim 2). Finally, we will determine the role of NAcC-projecting dopamine neurons in altered reward-related behavior in CNP. We will track behavior for consecutive weeks with operant tasks designed to capture RDoC-defined behavioral constructs relevant to depression symptoms. This longitudinal design will establish a high-resolution profile of altered reward valuation and sensitivity across the transition to CNP and will establish causal links between NAcC-projecting dopamine neuron adaptations and the emergence of behavioral changes (Aim 3). How adaptations within the mesolimbic dopamine system evolve over the transition from acute to chronic pain, and whether these adaptations drive affective symptoms in CNP is unknown. Our proposal will fill this gap by applying novel approaches to probe dopamine neuron function in vivo and ex vivo over the transition over acute to chronic phases post- nerve injury. It will also lay the foundation to reverse these adaptations as a therapeutic strategy for affective symptoms of CNP.
