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

 描述（由申请人提供）：药物成瘾的进展阶段通过临床观察和动物行为实验明确定义。认识到这些发展阶段主要来自于观察成瘾行为的外在迹象。理解药物成瘾的各个阶段所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，不同类型的神经元在药物成瘾过程中发挥着不同的作用。然而，详细的电路组织不同类型的细胞在NAC和相关的脑区尚未完全阐明。此外，在药物成瘾的进展过程中，其他脑区如何参与调节NAc中不同的神经元亚群尚未进行系统分析。这部分是因为我们缺乏有效的方法来监测神经适应在电路特定的方式在不同的大脑区域在同一时间的阶段进展到成瘾。利用小鼠可卡因成瘾作为模型系统，我提出了一种新的研究药物成瘾的范式，通过监测与NAc中不同细胞类型相关的脑回路中的神经适应， 每一个阶段的成瘾进展。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与NAc中不同细胞类型形成突触的神经元的全脑地图。首先，我们将阐明传入连接到不同类型的细胞在整个大脑的NAc。第二，我们将研究结构可塑性和突触在不同的大脑区域投射到每种细胞类型的NAc的可卡因成瘾的不同阶段在同一大脑中的同一时间的动态。通过这种方法，我们将填补可卡因成瘾研究中缺失的一些最重要的信息：哪些神经回路参与其中，以及随着成瘾的进展，它们在各个阶段都经历了哪些变化？了解成瘾不同阶段药物诱导的回路水平改变将为指导未来药物成瘾以及奖励回路作用的研究提供有价值的框架，最终导致开发更好的治疗策略。此外，这里用于神经回路的解剖学和功能表征的方法可用于研究任何分期进展的神经精神病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.