Investigating the ventral pallidum-ventral tegmental area circuit in cocaine relapse

点击翻译按钮获取中文摘要

Project Summary/Abstract: Rises in cocaine misuse and cocaine overdose deaths over the last decade illustrate the lack of therapeutic interventions for individuals with cocaine use disorder (CUD). With abstinence as the only treatment for cocaine cravings, a majority of individuals with CUD are vulnerable to relapse. The development of novel CUD therapeutics relies on a thorough understanding of the neural mechanisms that drive cocaine craving and relapse. Cocaine causes molecular adaptations within distinct neuronal subpopulations that leads to circuit- specific changes in neural activity. A critical node of the reward circuit is the ventral pallidum (VP), as it receives input from and projects to several regions that mediate cocaine-seeking behaviors. Activity from VP afferents to the ventral tegmental area (VTA-projecting VP neurons) is required for cocaine relapse; however, the cellular and molecular adaptations that occur within VTA-projecting VP neurons to promote cocaine-seeking, are unknown. To better understand the pathology of CUD, this proposal will investigate how changes in neuronal activity and gene expression within VTA-projecting VP neurons occur within cue-induced reinstatement to cocaine-seeking. Using cocaine intravenous self-administration (IVSA) and chemogenetics in mice, my preliminary data replicates a previous finding in rats that VTA-projecting VP neurons are required for reinstatement of cocaine-seeking. In this proposal, I will employ IVSA, cutting-edge in vivo biosensors, chemogenetics and molecular techniques to investigate the circuit-specific changes in VP neuronal activity and gene expression that occur during reinstatement to cocaine-seeking. I hypothesize that cocaine engages VTA- projecting VP neurons, leading to cocaine cue-induced 1) enhancement of VTA-projecting VP neuronal activity and 2) increases in synaptic gene expression that accompany drug-seeking and relapse. In Specific Aim 1, I will use fiber photometry to assess how cocaine-associated cues affected patterned calcium activity within VTA- projecting VP neurons during cue-induced reinstatement. I will also examine how chemogenetic inhibition of VTA-projecting VP neurons impacts changes in VTA-projecting VP calcium activity following the presentation of cocaine-associated cues. In Specific Aim 2, I will perform ribosomal immunoprecipitation with RNA-Sequencing to determine whether increases in synaptic gene expression within VTA-projecting VP neurons occurs following reinstatement to cocaine-seeking. Further, I will examine whether inhibiting VTA-projecting VP neuronal activity prevents reinstatement-induced changes in gene expression using chemogenetics and RNAScope. Together, these experiments will identify novel mechanisms within VTA-projecting VP neurons neurons that mediate reinstatement to cocaine-seeking. This proposal will also provide me with strong training in new research areas that will support my independent career path in science.