Defining the neural ensembles of cocaine addiction

定义可卡因成瘾的神经系统

• 批准号: 9907353
• 负责人: Kimberly C Thibeault
• 金额: $ 3.02万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907353
• 关键词: Ablation; Addictive Behavior; Affect; Animals; Automobile Driving; Behavior; Behavior Control; Behavioral; Brain region; Cells; Cocaine; Cocaine Abuse; Cocaine Dependence; Complex; Consumption; Cues; Data; Development; Disease; Drug Addiction; Enterobacteria phage P1 Cre recombinase; Fiber; Future; Genetic; Genetic Markers; Goals; Halorhodopsins; Heterogeneity; Immediate-Early Genes; Injections; Label; Lead; Learning; Mediating; Mediator of activation protein; Modeling; Mus; Neurobiology; Neurons; Nucleus Accumbens; Opsin; Optics; Pharmaceutical Preparations; Pharmacotherapy; Phase; Photometry; Play; Population; Process; Property; Public Health; Relapse; Research; Rewards; Role; Saline; Self Administration; Self Stimulation; Stimulus; Substance Use Disorder; Tamoxifen; Techniques; Training; Treatment Efficacy; Treatment outcome; Viral; Volition; Work; addiction; cell behavior; cell type; cocaine exposure; cocaine use; drug development; drug of abuse; drug seeking behavior; experimental study; genetic approach; improved; in vivo; learned behavior; neuromechanism; neuroregulation; new therapeutic target; novel; optogenetics; pre-clinical; promoter; reinforced behavior; relating to nervous system; targeted treatment; tool

Project summary Substance use disorder is a public health concern with no effective, long-lasting pharmacotherapies. A large amount of effort has been put into defining the neural basis of addictive behaviors as well as the factors that lead to the development of drug addiction. Past research has focused on the role of entire brain regions in mediating addiction and recently, with advances in genetic approaches, genetically defined cellular populations. However, recent work has shown that even within these defined populations, only a small percentage of cells are activated to a given stimulus. Thus, moving forward, it will be important to identify the role of functionally defined neural populations – termed ensembles – in addictive behaviors. Here, we aim to understand how ensembles in the nucleus accumbens (NAc) that are activated by cocaine encode information and drive volitional cocaine consumption. In this proposal, we will combine translational addiction models (mouse self-administration) with optical tools for recording (fiber photometry) and manipulating (optogenetics) functionally defined ensembles to elucidate what information is encoded within them and how they control complex behaviors. Together, this proposal will give me the technical and theoretical training to answer complex questions about the neural control of behavior and its dysregulation in substance use disorder. In Aim 1, I will define what aspects of cocaine- associated behaviors these cells encode by using fiber photometry to record from cocaine-activated ensembles in vivo while animals self-administer cocaine. In Aim 2, I will determine if these ensembles are sufficient to drive self-administration by allowing mice to perform optical self-stimulation tasks in ChR2-tagged cocaine-activated ensembles. Finally, in Aim 3, we will define how temporally specific activation or inhibition of these cells during specific stimuli alters self-administration. By photo-stimulating or -inhibiting these cocaine ensembles during self- administration, we can define the sufficiency and necessity of these neural populations in various aspects of drug-taking (acquisition, consumption, and drug seeking/relapse). These experiments will provide new information about the cell-specific populations that drive both initial drug taking as well as the behaviors that define substance use disorder. By focusing on functionally defined neuronal populations, we will discover subpopulations that would be unobservable when applying a priori broad genetic markers. Through these novel findings, we will learn more about the mechanisms that mediate progression to drug addiction in specific subpopulations so that we will be able, in the future, to decrease cocaine-taking behavior without producing addictive or aversive effects.

项目摘要 药物使用障碍是一个公共卫生问题，没有有效的，持久的药物治疗。一个大 付出了努力，以定义累加行为的神经基础以及领导的因素 吸毒成瘾的发展。过去的研究集中于整个大脑区域在中介中的作用 成瘾，最近，随着遗传方法的进步，遗传定义的细胞种群。然而， 最近的工作表明，即使在这些定义的人群中，只有一小部分细胞被激活 给定的刺激。向前迈进，确定功能定义的中性的作用将很重要 种群 - 被称为合奏 - 采用加性行为。在这里，我们旨在了解如何合奏 可卡因编码信息激活并驱动自愿可卡因激活的伏隔核（NAC） 消耗。在此提案中，我们将结合翻译成瘾模型（鼠标自我管理） 用于记录的光学工具（光纤光度法）和操纵（光遗传学）功能定义的合奏 阐明其中编码的信息以及它们如何控制复杂行为。一起，这个 提案将为我提供技术和理论培训，以回答有关神经控制的复杂问题 行为及其在药物使用障碍中的失调。在AIM 1中，我将定义可卡因的哪些方面 相关行为这些细胞通过使用光纤光度法编码从可卡因激活的合奏中记录 在体内，动物自我管理可卡因。在AIM 2中，我将确定这些集合是否足以驾驶 通过允许小鼠在CHR2标记的可卡因激活中执行光学自我刺激任务来进行自我管理 合奏。最后，在AIM 3中，我们将定义这些细胞在 特定的刺激改变了自我管理。通过刺激或抑制这些可卡因在自我期间 管理，我们可以在各个方面定义这些神经种群的安全性和必要性 吸毒（获取，消费和寻求/复发）。这些实验将提供新的 有关驱动初始药物服用的细胞特异性人群的信息以及 定义药物使用障碍。通过专注于功能定义的神经元种群，我们将发现 在应用先验广泛的遗传标记时，亚群将是不可观察的。通过这些小说 调查结果，我们将进一步了解有关在特定中介导吸毒进展的机制 亚群，以便我们将来能够降低可卡因的行为而不产生 加性或厌恶效果。