Investigating function of novel drug-induced synaptic changes in the VTA

 描述（由申请人提供）：药物滥用是一个重大的全球性问题，往往具有破坏性的社会后果。虽然旨在治疗药物成瘾的治疗方法主要集中在药物干预和同时进行的行为治疗，但在减少这一重大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）通路，该通路通常由腹侧被盖区（VTA）的神经元激活，其部分功能是发出奖励信号。然而，DA神经元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。在我博士后研究的最初几年里，使用一种新的基于狂犬病病毒的跨突触追踪方法，我构建了一个详细的VTA-DA神经元输入输出图，包括VTA-DA神经元特定亚群的输入。在随后的一系列初步实验中，我使用狂犬病病毒进行了全脑输入筛选，以确定在单次施用各种药物后发生的VTA-DA神经元突触变化的位点。 从这个屏幕的初步数据表明，某些抑制性输入（从苍白球外段，或GPe，和内侧壳的核丘脑）被改变了单剂量的可卡因，这些变化发生在腹侧被盖区-DA神经元投射到外侧壳的丘脑核丘脑。此外，这些变化发生在表现出行为敏感化的动物中，这表明这些输入可能在成瘾行为的这一方面被特别修改。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。 成瘾的自我管理模式。首先，我将研究从这些定义的突触到VTA-DA神经元的可塑性的本质。其次，我将使用这些变化的知识来指导体内光遗传学和化学遗传学操作，以试图预防或逆转可卡因自我施用时发生的药物诱导的行为改变。最后，在独立阶段，我将使用自我管理模型，但现在专注于外侧缰输入到中脑的可卡因戒断的发展和表达的作用。由于LHb包含独特的亚型，这些亚型投射到RMTg中的VTA-DA神经元或GABA神经元，因此我将分析自我管理和戒断对LHb-VTA-DA和LHb-RMTg-GABA连接的影响，每个输入在戒断中所起的作用，以及每个亚型的操作是否可以夸大或减轻戒断症状。 由于我的初步数据表明，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改变，这种技术在产生假设方面的巨大力量将非常有助于产生一个独立于我的博士后导师的独特研究计划。

 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.