Dissecting the role of ventral pallidal circuitry in cocaine seeking after the withdrawal

项目摘要 长期禁欲期间的药物渴望是导致反复循环的主要因素。 吸毒鉴于药物滥用日益普遍，我们必须获得 对神经回路可塑性和相关分子机制的清晰理解 特别是潜在的毒瘾腹侧苍白球（VP）是脑的主要输出结构。 中脑边缘奖赏回路，被认为是最终的共同途径， 动机处理通过中继信息从丘脑腹侧核（NAc）和 被盖区（VTA）到外侧缰（LHb）、VTA和丘脑底结构。然而，在这方面， 对药物成瘾中VP神经元的回路水平组织和功能知之甚少， 特别是在长期戒断后寻求毒品的情况下。所以我们会 从解剖学和功能上探讨VP的分子定义子集的神经适应 输出神经元使用可卡因自我管理模式在小鼠中，为了更好地 了解长期戒断后寻求可卡因的潜在机制。 为了实现这一点，我们建议研究特定的戒断诱导的神经适应， 通过使用包括光遗传学在内的多种尖端技术， 操纵，神经活动的体内监测，病毒介导的追踪，离体电生理学， 和药物成瘾的小鼠可卡因自我给药模型中的分子谱分析方法。 我们的初步数据表明，多巴胺受体3（Drd 3）信号转导选择性上调， 在从可卡因自我给药中戒断期间VP中， VP，但不是在NAc中，在长时间戒断后抑制可卡因寻求行为，但不是 蔗糖奖赏寻求，强烈表明VP Drd 3信号可能起主要作用 特别是可卡因引起的渴望和药物寻求行为。我们首先定义传入神经 和表达Drd 3的VP神经元的传出连接。其次，我们将检查电路- VP Drd 3神经元的特定神经适应及其在可卡因寻求中的作用。三是 研究VP Drd 3神经元活性如何调节VTA多巴胺能神经元活性， 可卡因自我给药后长时间戒断时NAc和VP中多巴胺的释放 使用最先进的成像技术这个项目的完成将大大 有益于提供一个框架，研究吸毒成瘾在特定回路的方式，以及 比如制定一个治疗毒瘾的策略。

PROJECT SUMMARY Drug craving during prolonged periods of abstinence is a major factor driving repeated cycles of drug abuse. In light of the increasing prevalence of drug abuse, it is imperative that we obtain a clear understanding of the neural circuit plasticity and associated molecular mechanisms underlying drug craving specifically. The ventral pallidum (VP) is the major output structure of the mesolimbic reward circuitry and is suggested to be the final common pathway for reward and motivational processing by relaying information from the nucleus accumbens (NAc) and ventral tegmental area (VTA) to the lateral habenula (LHb), VTA, and subthalamic structures. However, little is known about the circuit level organization and function of VP neurons in drug addiction, especially in the context of drug seeking following prolonged withdrawal. Therefore, we will anatomically and functionally probe the neural adaptations of a molecularly-defined subset of VP output neurons using the cocaine self-administration paradigm in mice, in order to better understand the mechanisms underlying cocaine seeking after a prolonged period of withdrawal. To accomplish this, we propose to study withdrawal-induced neural adaptations in specific subcircuits originating in the VP by using multiple cutting-edge techniques including optogenetic manipulation, in vivo monitoring of neural activity, viral-mediated tracing, ex vivo electrophysiology, and molecular profiling methods in a mouse cocaine self-administration model of drug addiction. Our preliminary data indicate that dopamine receptor 3 (Drd3) signaling is selectively upregulated in the VP during withdrawal from cocaine self-administration, and that knockdown of Drd3 in the VP, but not in the NAc, inhibits cocaine seeking behavior after prolonged withdrawal, but not sucrose reward seeking, strongly suggesting that VP Drd3 signaling may play a major role specifically in cocaine-induced craving and drug seeking behavior. We will first define the afferent and efferent connections of Drd3-expressing VP neurons. Second, we will examine the circuit- specific neural adaptations of VP Drd3 neurons and their role in cocaine seeking. Third, we will examine how VP Drd3 neuronal activity regulates VTA dopaminergic neuronal activity and dopamine release in NAc and VP during prolonged withdrawal from cocaine self-administration using cutting-edge imaging techniques. The accomplishment of this project will be greatly beneficial in providing a framework for studying drug addiction in a circuit-specific manner, as well as in developing a strategy for the treatment of drug addiction.