INVESTIGATING FUNCTION OF NOVEL DRUG-INDUCED SYNAPTIC CHANGES IN THE VTA

研究新型药物引起的 VTA 突触变化的功能

• 批准号: 9769671
• 负责人: KEVIN T BEIER
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769671
• 关键词: Acute; Addictive Behavior; Advisory Committees; Anatomy; Animals; Area; Award; Behavior Therapy; Behavioral; Biological Assay; Brain; Clinical; Cocaine; Combination Drug Therapy; Cues; Data; Development; Dopamine; Dose; Drug Addiction; Drug Screening; Drug abuse; Economic Burden; Electrophysiology (science); Equilibrium; Fellowship; Functional disorder; Genetic Techniques; Globus Pallidus; Goals; Habenula; Intervention; K-Series Research Career Programs; Knowledge; Lateral; Learning; Maintenance; Maps; Measures; Medial; Mentors; Midbrain structure; Modeling; Modification; Nature; Neurons; Nucleus Accumbens; Optics; Output; Paper; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Population; Procedures; Property; Prosencephalon; Publishing; Rabies virus; Recurrence; Relapse; Research; Rewards; Role; Self Administration; Signal Transduction; Site; Slice; Stress; Structure; Substance abuse problem; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Ventral Tegmental Area; Withdrawal; Withdrawal Symptom; Work; addiction; base; behavioral sensitization; career; cocaine use; design; dopaminergic neuron; drug abuse prevention; drug of abuse; drug relapse; experimental study; gamma-Aminobutyric Acid; genetic approach; genetic technology; in vivo; neuronal circuitry; novel; novel therapeutics; optogenetics; post-doctoral training; prevent; psychostimulant; public health relevance; reduce symptoms; response; social; virus genetics

 DESCRIPTION (provided by applicant): Drug abuse is a major global problem with often devastating societal consequences. While therapeutics designed to treat drug addiction have focused on medicinal intervention with concurrent behavioral therapy, much progress remains to be made in reducing this major social and economic burden. All drugs of abuse appear to work on the dopamine (DA) pathway in the brain, which is normally activated by neurons in the ventral tegmental area (VTA) that function, in part, to signal reward. However, DA neurons are not a homogenous population, but rather are composed of multiple subtypes with distinct functions. During the first few years of my postdoctoral fellowship, using a new rabies virus-based transsynaptic tracing approach, I constructed a detailed input-output map of VTA-DA neurons, including the inputs to specific subpopulations of VTA-DA neurons. In a subsequent set of pilot experiments, I conducted a brain-wide input screen using the rabies virus to identify the locus of synaptic changes onto VTA-DA neurons that occur after a single administration of a variety of drugs. Preliminary data from this screen suggest that certain inhibitory inputs (from the globus pallidus external segment, or GPe, and the medial shell of the nucleus accumbens) are altered by a single dose of cocaine, and that these changes occur specifically onto the VTA-DA neurons projecting to the lateral shell of the nucleus accumbens. In addition, these changes occur in animals that display behavioral sensitization, suggesting that these inputs may be specifically modified in this aspect of addictive behaviors. To more rigorously understand the roles of these inputs in addiction, I propose to analyze the roles of these synaptic adaptations in a self-administration model of addiction. First, I will examine the nature of the plasticity occurrng from these defined synapses onto VTA-DA neurons. Secondly, I will use the knowledge of these changes to direct optogenetic and chemogenetic manipulations in-vivo in an attempt to prevent or reverse the drug- induced behavioral alterations occurring with cocaine self-administration. Lastly, in the independent phase, I will use the self-administration model, but now focus on the role of lateral habenula inputs to the midbrain for the development and expression of cocaine withdrawal. As the LHb contains unique subtypes that project either to VTA-DA neurons or GABA neurons in the rostrotegmental area (RMTg), I will analyze the effects of self-administration and withdrawal on the LHbVTA-DA and LHbRMTg-GABA connections, the role that each input plays in withdrawal, and if manipulations of each subtype can either exaggerate or alleviate symptoms of withdrawal. As my preliminary data suggest that the rabies virus can be used as a non-biased technique to screen for drug-induced synaptic alterations, the immense power of this technique in generating hypotheses will be highly useful in generating a unique research plan independent from that of my postdoctoral mentor.

 描述(由申请人提供)：药物滥用是一个主要的全球性问题，往往具有破坏性的社会后果。虽然治疗药物成瘾的治疗方法侧重于药物干预和同时进行行为治疗，但在减少这一主要的社会和经济负担方面仍需取得很大进展。所有滥用药物似乎都作用于大脑中的多巴胺(DA)途径，该途径通常由腹侧被盖区(VTA)的神经元激活，部分功能是发出奖励信号。然而，DA神经元并不是一个同质的群体，而是由具有不同功能的多个亚型组成。在我的博士后生涯的头几年里，我使用一种新的基于狂犬病病毒的跨突触追踪方法，构建了一张详细的VTA-DA神经元的输入-输出图，包括VTA-DA神经元特定亚群的输入。在随后的一系列试点实验中，我使用狂犬病病毒进行了一次全脑输入屏幕，以识别在单一给药后VTA-DA神经元上发生的突触变化的位置。来自这个屏幕的初步数据表明，某些抑制输入(来自苍白球外节或GPE，以及伏隔核内侧壳)可以被单剂量的可卡因改变，并且这些变化专门发生在投射到伏隔核外侧壳的VTA-DA神经元上。此外，这些变化发生在表现出行为敏感化的动物身上，这表明这些输入可能在成瘾行为的这一方面进行了专门的修改。为了更严格地理解这些输入在成瘾中的作用，我建议分析这些突触适应在成瘾中的作用 一种上瘾的自我管理模式。首先，我将研究从这些已定义的突触到VTA-DA神经元发生的可塑性的本质。其次，我将利用这些变化的知识来指导体内的光遗传和化学遗传操作，试图防止或逆转可卡因自我给药引起的药物诱导的行为变化。最后，在独立阶段，我将使用自我给药模型，但现在集中在外侧缰核输入到中脑对可卡因戒断的发展和表达的作用。由于LHb包含投射到Vta-DA神经元或旋转被盖区(RMTg)的GABA神经元的独特亚型，我将分析自我给药和戒断对LHbVta-DA和LHbRMTg-GABA连接的影响，每种输入在戒断中所起的作用，以及每种亚型的操作是否可以夸大或缓解戒断症状。我的初步数据表明，狂犬病病毒可以作为一种无偏见的技术来筛选药物诱导的突触变化，这种技术在生成假设方面的巨大能力将在生成独立于我博士后导师的独特研究计划方面非常有用。