Dissecting circuit- and stage-specific neural adaptations in an animal model of drug addiction

 描述(由申请人提供)：临床观察和动物行为实验很好地定义了药物成瘾的进行性阶段。认识到这些发展阶段很大程度上是通过观察上瘾行为的外部迹象来实现的。在了解药物成瘾的各个阶段时，缺少的是负责特定阶段症状的神经回路的知识。许多研究表明，伏隔核(NAC)中不同类型的细胞在药物成瘾中起不同的作用。然而，不同类型细胞在NAC及其相关脑区的详细电路组织尚未完全阐明。此外，在发展成药物成瘾的过程中，其他大脑区域如何参与调节NAC中不同的神经元亚群还没有得到系统的分析。这在一定程度上是因为我们缺乏有效的方法，在不同的大脑区域以特定于电路的方式同时监测神经适应，同时进入成瘾的阶段。以小鼠可卡因成瘾为模型系统，我提出了一种新的研究药物成瘾的范式，通过监测与NAC不同细胞类型相关的脑回路中的神经适应 成瘾发展的每一个阶段。为了实现这一点，我们使用表达荧光标记或突触标记的单突触狂犬病病毒系统来生成全脑范围的神经元地图，这些神经元形成与NAC中不同细胞类型的突触。首先，我们将阐明NAC中不同类型细胞在整个大脑中的传入联系。其次，我们将研究不同脑区的结构可塑性和突触在同一大脑的不同时间投射到不同类型的NAC的结构可塑性和突触的动力学。通过这种方式，我们将填补可卡因成瘾研究中缺失的一些最重要的信息：哪些神经回路参与，以及随着成瘾的进展，它们在不同阶段经历了什么修改？了解药物在成瘾不同阶段引起的回路水平的改变将为指导未来对药物成瘾的研究以及奖赏回路的作用提供一个有价值的框架，最终导致开发出更好的治疗这种精神障碍的策略。此外，这里使用的神经回路的解剖学和功能表征方法可以用于研究任何阶段性进展的神经精神病学或神经退行性疾病的模型。

 DESCRIPTION (provided by applicant): Progressive stages of drug addiction are well defined by clinical observations and animal behavior experiments. Recognizing these stages of progression comes largely from observing outward signs of addicted behaviors. What is missing from understanding stages of drug addiction is the knowledge of neural circuits responsible for stage-specific symptoms. Many studies suggested that distinct cell types in nucleus accumbens (NAc) plays different roles in the drug addiction. However, the detailed circuit organization of different cell types in NAc and associated brain areas has not been fully elucidated. Moreover, how other brain areas engaged to modulate different subpopulations of neurons in NAc during the progression into drug addiction has not been systemically analyzed. This is partly because we lack the efficient methods to monitor the neural adaptation in circuit-specific manners in different brain areas at the same time as stages progress towards addiction. Using cocaine addiction in mice as a model system, I propose a new paradigm for studying drug addiction by monitoring the neural adaptation in brain circuitries related to different cell types in NAc during each stage of addiction progression. To achieve this, we use a monosynaptic rabies virus system expressing fluorescent marker or synaptic markers to generate brain-wide maps of neurons that form synapses with different cell types in NAc. First, we will elucidate afferent connections to different cell types in NAc in whole brain. Second, we will examine the dynamics of structural plasticity and synapses in different brain areas projecting to each cell type of NAc t the different stages of cocaine addiction at the same time in the same brain. By this means we will fill in some of the most important information missing in cocaine addiction research: which neural circuits engage, and what modifications do they undergo from stage to stage as addiction progresses? Understanding drug-induced circuit level modifications at different stages of addiction will provide a valuable framework for guiding future studies on drug addiction as well as the roles of reward circuitry, which eventually lead to develop better therapeutic strategy for this mental disorder. Furthermore, the approach used here for the anatomical and functional characterization of neural circuitry can be used to investigate models of any neuropsychiatric or neurodegenerative disease that progresses in stages.