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

• 批准号: 10296721
• 负责人: Hisashi Umemori
• 金额: $ 86.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10296721
• 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

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.

项目摘要 多巴胺（DA）对许多行为都很重要，如动机，学习和运动。故障 DA信号与各种精神和运动症状有关，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。虽然DA调节 在各种行为中，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），实际和预测奖励值之间的差异。然而，最近，我们和其他 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， 不同的功能。我们发现，DA在前纹状体（AS），中央和后纹状体（CS/PS）， 纹状体（TS）的“尾”信号典型RPE，调节技能的执行，或信号威胁预测错误， 分别因此，从中脑到AS、CS/PS和TS的多巴胺能投射必须是 差异和精确地建立它们来适当地调节我们的大脑功能。然而， 以及在纹状体中建立特异性多巴胺能连接的分子机制， 未知为了解决这个问题，我们已经寻找突触，嗜同性细胞粘附分子， 在AS、CS/PS和TS中差异表达。我们鉴定了三种原钙粘蛋白（PCDH）， PCDH 17、PCDH 10和PCDH 19分别在AS、CS/PS或TS中选择性表达， 发展和成人。此外，在中脑中，PCDH 17、10和19由DA神经元表达 分别投射到AS、CS/PS或TS。基于这些表达模式，我们假设 PCDH 17、10和19分别是AS-、CS/PS-和TS-投射DA神经元的分子代码， 并且它们在功能分离的DA回路的建立中起着关键作用。为了验证这些想法 我们已经产生了新的小鼠品系，其中Cre在Pcdh启动子下表达， （无效）和条件性敲除（KO）小鼠中的三种PCDH。使用这些鼠标线，我们建议 目的：目的1：确定PCDH 17、10和19是否是功能分离DA的分子密码 成年人的神经元目的2：研究多巴胺能神经元失活和激活对PCDH表达的影响 在不同的发展阶段。目的3：检测PCDH蛋白在建立人肝癌细胞系中的作用。 具体联系方式我们将使用分子/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 技术来实现这些目标。我们的工作将从分子上定义功能不同的DA回路，并揭示 特定的多巴胺回路是如何在哺乳动物大脑中建立的PCDH 17/10/19涉及不同的疾病： PCDH 17在情绪障碍和精神分裂症中，PCDH 10在自闭症和强迫症中，PCDH 19在癫痫和 人格障碍因此，我们的研究也可能提供特定DA回路与某些疾病之间的联系 并提出了治疗这些破坏性疾病的新策略。