Molecular Codes for the Establishment of Functionally Segregated Dopaminergic Circuits

建立功能分离的多巴胺能回路的分子密码

基本信息

批准号：
10415208
负责人：
Hisashi Umemori
金额：
$ 80.48万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415208
关键词：
Address Adult Anatomy Anterior Area Attention deficit hyperactivity disorder Axon Behavior Behavioral Biological Brain Cell Adhesion Molecules Cells Code Corpus striatum structure Data Defect Development Disease Dopamine Drug Addiction Electrons Electrophysiology (science)Emotional disorder Environment Epilepsy Event Exhibits Goals Histologic Image Knockout Mice Learning Link Maintenance Mediating Microscopic Midbrain structure Molecular Mood Disorders Motivation Movement Mus Neurons Parkinson Disease Pattern Personality Disorders Pharmaceutical Preparations Physiological Physiology Play Property Proteins Regulation Rewards Role Schizophrenia Signal Transduction Stimulus Synapses Tail Techniques Testing Time Work autism spectrum disorder base conditional knockout critical period differential expression dopaminergic neuron experience flexibility in vivo interdisciplinary approach motivated behavior motor symptom mouse genetics neuropsychiatric disorder novel novel strategies promoter protocadherin 10 protocadherin 19 psychiatric symptom relating to nervous system response selective expression skills synaptogenesis

项目摘要

PROJECT SUMMARY Dopamine (DA) is important for many behaviors such as motivation, learning, and movement. Malfunction of DA signaling is related to various psychiatric and motor symptoms, and DA-related drugs are commonly used to treat schizophrenia, ADHD, OCD, autism, personality disorders, and mood disorders. Although DA regulates various behaviors, it had been believed that the role of DA neurons is uniform: to signal "reward prediction error" (RPE), the discrepancy between actual and predicted reward value. Recently however, we and others showed that DA neurons projecting to different regions in the striatum exhibit distinct properties and serve distinct functions. We found that DA in the anterior striatum (AS), central and posterior striatum (CS/PS), and `tail' of the striatum (TS) signal canonical RPE, regulate the execution of skills, or signal threat prediction error, respectively. Therefore, dopaminergic projections from the midbrain to the AS, CS/PS, and TS must be differentially and precisely established for them to regulate our brain functions properly. However, the manner and molecular mechanisms by which specific dopaminergic connections are established in the striatum are unknown. To address this question, we have searched for synaptic, homophilic cell-adhesion molecules that are differentially expressed in the AS, CS/PS, and TS. We identified that three Protocadherins (PCDHs), PCDH17, PCDH10, and PCDH19, are selectively expressed in the AS, CS/PS, or TS, respectively, during development and in adults. Furthermore, in the midbrain, PCDH17, 10, and 19 are expressed by DA neurons projecting to the AS, CS/PS, or TS, respectively. Based on these expression patterns, we hypothesize that PCDH17, 10, and 19 are the molecular codes for the AS-, CS/PS-, and TS-projecting DA neurons, respectively, and that they play critical roles for the establishment of functionally segregated DA circuits. To test these ideas we have generated novel mouse lines in which Cre is expressed under the Pcdh promoters, and constitutive (null) and conditional knockout (KO) mice for each of the three PCDHs. Using these mouse lines, we propose to: Aim 1: Determine whether PCDH17, 10, and 19 are the molecular codes for functionally segregated DA neurons in adults. Aim 2: Investigate the effects of inactivation and activation of PCDH-expressing DA neurons during various stages of development. Aim 3: Examine the role of PCDH proteins in the establishment of specific DA connections. We will use interdisciplinary approaches with molecular/cell biological, histological, mouse genetic, electron microscopic, electrophysiological, in vivo recording/imaging, and behavioral techniques to address these aims. Our work will molecularly define functionally distinct DA circuits and reveal how specific DA circuits establish in the mammalian brain. PCDH17/10/19 are implicated in different disorders: PCDH17 in mood disorders and schizophrenia, PCDH10 in autism and OCD, and PCDH19 in epilepsy and personality disorders. Thus, our study may also provide a link between specific DA circuits to certain disorders and suggest novel strategies to treat these devastating disorders.

项目概要多巴胺 (DA) 对于许多行为（例如动机、学习和运动）很重要。故障 DA信号传导与多种精神和运动症状相关，DA相关药物是常用药物治疗精神分裂症、多动症、强迫症、自闭症、人格障碍和情绪障碍。尽管 DA 规定各种行为，人们一直认为 DA 神经元的作用是统一的：发出“奖励预测”信号错误”（RPE），实际奖励值与预测奖励值之间的差异。然而最近，我们和其他人表明投射到纹状体不同区域的 DA 神经元表现出不同的特性并发挥作用不同的功能。我们发现 DA 存在于前纹状体 (AS)、中央和后纹状体 (CS/PS) 以及纹状体（TS）的“尾部”发出规范的 RPE 信号，调节技能的执行，或发出威胁预测错误的信号，分别。因此，从中脑到 AS、CS/PS 和 TS 的多巴胺能投射必须是为它们建立差异化和精确的机制来正确调节我们的大脑功能。然而，方式纹状体中建立特定多巴胺能连接的分子机制是未知。为了解决这个问题，我们寻找了突触、同质细胞粘附分子在 AS、CS/PS 和 TS 中差异表达。我们确定了三种原钙粘蛋白 (PCDH)， PCDH17、PCDH10 和 PCDH19 分别在 AS、CS/PS 或 TS 中选择性表达，发育和成人。此外，在中脑中，PCDH17、10和19由DA神经元表达分别投影到 AS、CS/PS 或 TS。基于这些表达模式，我们假设 PCDH17、10和19分别是AS-、CS/PS-和TS-投射DA神经元的分子代码，它们对于建立功能隔离的 DA 电路起着关键作用。为了测试这些想法我们已经生成了新的小鼠品系，其中 Cre 在 Pcdh 启动子下表达，并且组成型对于三种 PCDH 中的每一种，（无效）和条件敲除（KO）小鼠。使用这些鼠标线，我们建议目标 1：确定 PCDH17、10 和 19 是否是功能分离 DA 的分子代码成人的神经元。目标 2：研究表达 PCDH 的 DA 神经元失活和激活的影响在各个发展阶段。目标 3：检查 PCDH 蛋白在建立特定的 DA 连接。我们将使用分子/细胞生物学、组织学、小鼠遗传学、电子显微镜、电生理学、体内记录/成像和行为学实现这些目标的技术。我们的工作将从分子角度定义功能不同的 DA 电路并揭示特定的 DA 回路如何在哺乳动物大脑中建立。 PCDH17/10/19 与不同的疾病有关： PCDH17 治疗情绪障碍和精神分裂症，PCDH10 治疗自闭症和强迫症，PCDH19 治疗癫痫和人格障碍。因此，我们的研究还可能提供特定 DA 回路与某些疾病之间的联系并提出治疗这些破坏性疾病的新策略。