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

项目总结 长期戒毒期间的药物渴求是导致反复戒毒周期的主要因素 吸毒。鉴于药物滥用日益猖獗，我们必须获得一个 清楚了解神经回路可塑性及其相关的分子机制 特别是潜在的毒瘾。腹侧苍白球(VP)是丘脑的主要输出结构。 中脑边缘奖赏回路，被认为是奖赏的最终共同途径。 伏隔核(NAC)和腹侧信息传递的动机加工 被盖区(VTA)至外侧缰核(LHb)、VTA和丘脑下部结构。然而， 关于VP神经元在药物成瘾中的电路水平组织和功能知之甚少， 特别是在长期戒毒后寻求毒品的情况下。因此，我们将 从解剖学和功能学的角度探讨VP分子亚群的神经适应 在小鼠中使用可卡因自我给药范式输出神经元，以便更好地 了解长期戒毒后寻求可卡因的机制。 为了实现这一点，我们建议研究戒断诱导的神经适应。 使用包括光遗传在内的多种尖端技术，在VP中产生子电路 操纵，神经活动的体内监测，病毒介导的追踪，体外电生理学， 和分子图谱方法在可卡因药物成瘾小鼠自我给药模型中的应用。 我们的初步数据表明，多巴胺受体3(Drd3)信号选择性上调 在戒断可卡因自我给药期间，在VP中，以及在 VP，但不是在NAC，抑制长期戒断后的可卡因寻求行为，但不是 蔗糖奖赏寻求，强烈提示VP Drd3信号可能起主要作用 尤其是可卡因引发的渴求和寻求毒品的行为。我们将首先定义传入 表达DRD3的VP神经元的传出联系。第二，我们将研究电路- VPDrd3神经元的特异性神经适应及其在寻找可卡因中的作用。第三，我们将 研究VP Drd3神经元活动如何调节VTA多巴胺能神经元活动和 长时间戒断可卡因时NAc和Vp的多巴胺释放 使用尖端的成像技术。这项工程的完成将极大地 也有利于提供以特定于电路的方式研究吸毒成瘾的框架 就像制定治疗药物成瘾的战略一样。

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.