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

剖析腹侧苍白球回路在可卡因戒断后寻求的作用

• 批准号: 10634528
• 负责人: Byungkook Lim
• 金额: $ 35.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634528
• 关键词: Abstinence; Addictive Behavior; Anatomy; Area; Automobile Driving; Behavior; Brain; Chronic; Cocaine; Cocaine Dependence; Cocaine withdrawal; Communication; Data; Dimensions; Dopamine; Dopamine Receptor; Drug Addiction; Drug Modelings; Drug abuse; Electrophysiology (science); Fiber; Fluorescent in Situ Hybridization; Globus Pallidus; Goals; Habenula; Imaging Techniques; Lateral; Lesion; Light; Measurement; Mediating; Methods; Midbrain structure; Modeling; Molecular; Molecular Profiling; Monitor; Motivation; Mus; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Photometry; Play; Population; Prevalence; Process; Property; Rewards; Role; Satiation; Self Administration; Signal Pathway; Signal Transduction; Stressful Event; Structure; Subthalamic structure; Synapses; System; Techniques; Technology; Transgenic Mice; Ventral Tegmental Area; Viral; Withdrawal; cocaine seeking; cocaine self-administration; cocaine use; conditioned place preference; craving; dopaminergic neuron; drug craving; drug of abuse; drug seeking behavior; feeding; genetic manipulation; in vivo; in vivo monitoring; insight; knock-down; neural; neural circuit; neuroadaptation; neuromechanism; neuronal circuitry; optogenetics; response; reward circuitry; reward processing; sensor; small hairpin RNA; targeted treatment; therapeutic development; tool; treatment strategy

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.

项目概要 长时间戒断期间的药物渴望是导致重复周期的主要因素 药物滥用。鉴于药物滥用现象日益普遍，我们必须获得 清楚地了解神经回路的可塑性和相关的分子机制 特别是潜在的药物渴望。腹侧苍白球（VP）是大脑的主要输出结构 中脑边缘奖励回路被认为是奖励和奖励的最终共同途径 通过传递来自伏隔核 (NAc) 和腹侧的信息进行动机处理 被盖区 (VTA) 到外侧缰核 (LHb)、VTA 和丘脑底结构。然而， 关于毒瘾中 VP 神经元的回路水平组织和功能知之甚少， 尤其是在长期戒断后寻求药物的情况下。因此，我们将 从解剖学和功能上探讨分子定义的 VP 子集的神经适应 使用小鼠可卡因自我管理范式输出神经元，以便更好地 了解长期戒断后寻找可卡因的潜在机制。 为了实现这一目标，我们建议研究特定的戒断诱导的神经适应 源自 VP 的子电路采用多种尖端技术，包括光遗传学 操作、体内神经活动监测、病毒介导的追踪、离体电生理学、 以及小鼠可卡因药物成瘾自我给药模型中的分子分析方法。 我们的初步数据表明多巴胺受体 3 (Drd3) 信号传导选择性上调 在从可卡因自我给药戒断期间的 VP 中，以及 Drd3 的敲低 VP（但不在 NAc 中）抑制长期戒断后的可卡因寻求行为，但不抑制 蔗糖奖励寻求，强烈表明 VP Drd3 信号传导可能发挥重要作用 特别是可卡因引起的渴望和寻求毒品的行为。我们首先定义传入 以及表达 Drd3 的 VP 神经元的传出连接。其次，我们将检查电路 - VP Drd3 神经元的特定神经适应及其在可卡因寻找中的作用。第三，我们将 检查 VP Drd3 神经元活动如何调节 VTA 多巴胺能神经元活动和 长时间戒断可卡因自我给药期间 NAc 和 VP 中多巴胺的释放 使用尖端的成像技术。该项目的完成将极大 也有利于提供一个以特定回路方式研究毒瘾的框架 就像制定治疗毒瘾的策略一样。

项目成果

Ventral pallidum DRD3 potentiates a pallido-habenular circuit driving accumbal dopamine release and cocaine seeking.

• DOI: 10.1016/j.neuron.2021.05.002
• 发表时间: 2021-07-07
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Pribiag, Horia;Shin, Sora;Wang, Eric Hou-Jen;Sun, Fangmiao;Datta, Paul;Okamoto, Alexander;Guss, Hayden;Jain, Akanksha;Wang, Xiao-Yun;De Freitas, Bruna;Honma, Patrick;Pate, Stefan;Lilascharoen, Varoth;Li, Yulong;Lim, Byung Kook
• 通讯作者: Lim, Byung Kook

Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits.

• DOI: 10.1038/s41593-021-00810-y
• 发表时间: 2021-04
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Lilascharoen V;Wang EH;Do N;Pate SC;Tran AN;Yoon CD;Choi JH;Wang XY;Pribiag H;Park YG;Chung K;Lim BK
• 通讯作者: Lim BK

Flexible scaling and persistence of social vocal communication.

社会声音交流的灵活缩放和持久性。

• DOI: 10.1038/s41586-021-03403-8
• 发表时间: 2021-05
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Chen, Jingyi;Markowitz, Jeffrey E.;Lilascharoen, Varoth;Taylor, Sandra;Sheurpukdi, Pete;Keller, Jason A.;Jensen, Jennifer R.;Lim, Byung Kook;Datta, Sandeep Robert;Stowers, Lisa
• 通讯作者: Stowers, Lisa

Thalamic Retrieval of Opioid Memories.

• DOI: 10.1016/j.neuron.2020.09.006
• 发表时间: 2020-09-23
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Pribiag H;Lim BK
• 通讯作者: Lim BK

Early adversity promotes binge-like eating habits by remodeling a leptin-responsive lateral hypothalamus-brainstem pathway.

• DOI: 10.1038/s41593-022-01208-0
• 发表时间: 2023-01
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Shin, Sora;You, In-Jee;Jeong, Minju;Bae, Yeeun;Wang, Xiao-Yun;Cawley, Mikel Leann;Han, Abraham;Lim, Byung Kook
• 通讯作者: Lim, Byung Kook