Molecular Codes for the Establishment of Functionally Segregated Dopaminergic Circuits

项目总结 多巴胺(DA)对许多行为如动机、学习和运动都很重要。的故障。 DA信号与各种精神和运动症状有关，与DA相关的药物是常用的药物 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。尽管地方检察官规定 在不同的行为中，人们一直认为DA神经元的作用是一致的：发出信号 误差“(RPE)，实际奖励值和预测奖励值之间的差异。然而，最近，我们和其他人 结果表明，投射到纹状体不同区域的DA神经元表现出不同的特性和服务 不同的功能。我们在前纹状体(AS)、中央纹状体(CS/PS)和后纹状体(CS/PS)发现了DA。 ‘尾’纹状体(TS)信号规范的RPE，调节技能的执行，或信号威胁预测错误， 分别进行了分析。因此，从中脑到AS、CS/PS和TS的多巴胺能投射必须是 不同和精确地建立了它们来适当地调节我们的大脑功能。然而，这种方式 在纹状体中建立特定多巴胺能联系的分子机制是 未知。为了解决这个问题，我们已经寻找了突触的、嗜同型的细胞黏附分子 在AS、CS/PS和TS中有差异表达。我们鉴定出三种原钙粘附素(PCDH)， PCDH17、PCDH10和PCDH19分别在AS、CS/PS或TS中选择性地表达 在发育和成人中。此外，在中脑，PCDH17、10和19由DA神经元表达 分别投影到AS、CS/PS或TS。根据这些表达模式，我们假设 PCDH17、10和19分别是AS、CS/PS和TS投射的DA神经元的分子密码。 它们在建立功能隔离的DA电路方面发挥着关键作用。为了检验这些想法 我们已经建立了新的小鼠系，在其中Cre在Pcdh启动子下表达，并构成 (Null)和条件性基因敲除(KO)小鼠，每种PCDH。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的分子编码 成人的神经元。目的2：研究PCDH表达的DA神经元的失活和激活效应 在不同的发展阶段。目的3：研究PCDH蛋白在建立 特定的DA连接。我们将使用跨学科的方法与分子/细胞生物学，组织学， 小鼠遗传学、电子显微镜、电生理、活体记录/成像和行为 解决这些目标的技术。我们的工作将从分子上定义不同的DA电路，并揭示 哺乳动物大脑中特定的DA回路是如何建立的。PCDH17/10/19与不同的疾病有关： PCDH17用于情绪障碍和精神分裂症，PCDH10用于自闭症和强迫症，PCDH19用于癫痫和 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。

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.