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

剖析毒瘾动物模型中特定回路和阶段的神经适应

• 批准号: 8952009
• 负责人: Byungkook Lim
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952009
• 关键词: Abstinence; Affect; Afferent Neurons; American; Amygdaloid structure; Animal Behavior; Animal Model; Area; Behavior; Biological Models; Brain; Cells; Chronic; Chronic stress; Clinical; Cocaine; Cocaine Dependence; DLG4 gene; Data; Dendritic Spines; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Effectiveness; Equilibrium; Excitatory Synapse; Exhibits; Exposure to; FOS gene; Future; Glutamates; Hippocampus (Brain); Immediate-Early Genes; Individual; Interneurons; Knowledge; Label; Lead; Maps; Medial; Mediating; Mental disorders; Methods; Modeling; Modification; Monitor; Mus; Neurodegenerative Disorders; Neurons; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Play; Population; Prefrontal Cortex; Process; Proteins; Rabies; Rabies virus; Relapse; Reporting; Research; Rewards; Role; Shapes; Signal Transduction; Staging; Symptoms; Synapses; Synaptic plasticity; System; Technology; Therapeutic; Time; Transgenic Animals; Viral; Viral Vector; Virus; Withdrawal; addiction; brain circuitry; cell type; cholinergic; cholinergic neuron; cocaine exposure; cost; density; design; drug of abuse; in vivo; neural circuit; neuroadaptation; neuropsychiatry; novel; public health relevance; recombinase; research study; response; reward circuitry

 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.

 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得到了很好的定义。认识到这些进展阶段主要来自于观察成瘾行为的外在迹象。理解毒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，伏隔核（NAc）中不同的细胞类型在药物成瘾中发挥着不同的作用。然而，NAc 和相关大脑区域中不同细胞类型的详细电路组织尚未完全阐明。此外，在药物成瘾过程中，其他大脑区域如何参与调节 NAc 中不同的神经元亚群尚未得到系统分析。部分原因是我们缺乏有效的方法来监测不同大脑区域在成瘾阶段进展的同时以特定回路方式的神经适应。使用小鼠可卡因成瘾作为模型系统，我提出了一种新的范式，通过监测与 NAc 中不同细胞类型相关的大脑回路的神经适应来研究药物成瘾。 成瘾进展的每个阶段。为了实现这一目标，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神经元图，这些神经元与 NAc 中的不同细胞类型形成突触。首先，我们将阐明全脑 NAc 中不同细胞类型的传入连接。其次，我们将检查不同大脑区域的结构可塑性和突触的动态，在同一大脑中同时投射到可卡因成瘾的不同阶段的每种 NAc 细胞类型。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：哪些神经回路参与其中，以及随着成瘾的进展，它们在不同阶段会经历哪些修改？了解成瘾不同阶段药物诱导的回路水平的改变将为指导未来对药物成瘾以及奖励回路的作用的研究提供一个有价值的框架，从而最终为这种精神障碍制定更好的治疗策略。此外，此处用于神经回路解剖和功能表征的方法可用于研究分阶段进展的任何神经精神或神经退行性疾病的模型。