Simultaneous and Bidirectional Chemogenetic Control of Mesolimbic and Nigrostriatal Circuits

中脑边缘和黑质纹状体回路的同步和双向化学遗传学控制

• 批准号: 9530043
• 负责人: Marc G. Caron
• 金额: $ 23.96万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9530043
• 关键词: Address; Animal Model; Antipsychotic Agents; Autistic Disorder; Behavior; Behavior Control; Behavioral; Biochemical; Bipolar Disorder; Brain; Brain Diseases; Complex; Disease; Dopamine; Electrophysiology (science); Elements; Engineering; Financial compensation; Foundations; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic; Gilles de la Tourette syndrome; Goals; Human; Immunohistochemistry; Individual; Investigation; Laboratories; Link; Literature; Logic; Maps; Measures; Mental disorders; Methods; Modality; Modeling; Modification; Molecular; Molecular Biology; Molecular Genetics; Mono-S; Mutation; Neuromodulator; Neurons; Obsessive-Compulsive Disorder; Outcome; Parkinson Disease; Pharmacology; Play; Procedures; Property; Reagent; Research Domain Criteria; Rodent Model; Role; Schizophrenia; Selective Serotonin Reuptake Inhibitor; Serotonin; Synapses; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Validation; Variant; base; burden of illness; design; designer receptors exclusively activated by designer drugs; dopamine system; experimental study; functional status; gene function; genetic approach; genome wide association study; innovation; loss of function; mouse model; neural circuit; neurochemistry; neuron development; neuropsychiatric disorder; neuropsychiatry; optogenetics; receptor function; recombinase; remote control; theories; tool

ABSTRACT Most mental disorders have strong underlying genetic component, with many disease-associated variants occurring in genes involved in neuronal development and synaptic transmission. This suggests that deficits in cellular mechanisms may ultimately alter brain-circuit connectivity to yield dysfunctions in specific behavioral domains. Consistent with the RDoC framework, several independent circuit deficits likely synergize to create a distinct emergent state in large-scale networks ultimately yielding mental disorders. While multiple rodent models have begun to link circuit function with behavior, modeling these complex network-level alterations has been largely intractable with current optogenetic and chemogenetic tools that only target individual circuit elements of complex networks. This proposal presents a solution to this problem by developing and validating a new tool to simultaneously and bidirectionally control distinct brain circuits via chemogenetics. We then apply these reagents to two dopamine (DA) circuits in the brain, the nigrostriatal and mesocorticolimbic circuits. The resulting model will be characterized behaviorally and with state-of-the-art electrophysiological techniques to measure the functional consequences of concurrent bidirectional modulation of DA circuity. In Aim 1, we present the design and validation experiments necessary to generate and verify the correct function of these reagents. In Aim 2, we will use these reagents to associate DA circuit functional status with specific behavioral domain dysfunctions through the use of electrophysiological ensemble recordings during behavioral tasks. After completing these aims, we will have established proof-of-concept that a mouse model can recapitulate distinct and simultaneous modifications in two brain circuits that can be used to identify synergistic or antagonistic interactions between these brain circuits at the network level.

摘要 大多数精神障碍都有很强的潜在遗传成分，有许多与疾病相关的变种 发生在涉及神经元发育和突触传递的基因中。这表明，中国的赤字 细胞机制可能最终改变大脑电路的连接，从而导致特定行为的功能障碍 域名。与RDoC框架一致，几个独立的电路缺陷可能会协同作用，创建一个 大规模网络中不同的紧急状态最终会导致精神障碍。而多种啮齿动物模型 已经开始将电路功能与行为联系起来，对这些复杂的网络级变化进行建模已经 目前的光遗传和化学遗传工具只针对单个电路元件，很难解决 复杂的网络。该提案通过开发和验证一个新工具来解决此问题 同时，通过化学遗传学双向控制不同的大脑回路。然后我们用这些试剂 与大脑中的两个多巴胺(DA)回路有关，即黑质纹状体和中皮质边缘回路。由此产生的模型 将被描述为行为特征，并使用最先进的电生理技术来测量 DA回路的并发双向调制的功能后果。在目标1中，我们介绍了设计 以及产生和验证这些试剂的正确功能所需的验证实验。在目标2中，我们 将使用这些试剂将DA回路功能状态与特定行为域功能障碍联系起来 通过在行为任务中使用电生理整体记录。在完成这些任务后 目标，我们将建立概念证明，即小鼠模型可以概括不同的和同时的 两个大脑回路中的修饰，可用于识别相互之间的协同或拮抗作用 这些大脑在网络层面上进行循环。