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.

抽象的 大多数精神疾病都有很强的潜在遗传成分，有许多与疾病相关的变异 发生在涉及神经元发育和突触传递的基因中。这表明赤字 细胞机制可能最终会改变大脑回路的连接，从而产生特定行为的功能障碍 域。与 RDoC 框架一致，几个独立的电路缺陷可能协同作用以创建一个 大规模网络中独特的紧急状态最终会导致精神障碍。虽然多种啮齿动物模型 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改变进行建模 目前的光遗传学和化学遗传学工具在很大程度上难以处理，这些工具仅针对单个电路元件 复杂的网络。该提案通过开发和验证一种新工具来解决这个问题 通过化学遗传学同时双向控制不同的大脑回路。然后我们应用这些试剂 大脑中的两个多巴胺（DA）回路，黑质纹状体和中皮质边缘回路。得到的模型 将通过行为特征和最先进的电生理技术来测量 DA 电路并发双向调制的功能后果。在目标 1 中，我们展示了设计 生成和验证这些试剂的正确功能所必需的验证实验。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 通过在行为任务期间使用电生理学整体记录。完成这些之后 目标是，我们将建立概念验证，即小鼠模型可以概括不同的和同时的 两个大脑回路的修改可用于识别之间的协同或拮抗相互作用 这些大脑回路在网络层面上。