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: 10618351
• 负责人: Hisashi Umemori
• 金额: $ 76.24万
• 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/10618351
• 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; conditional knockout; critical period; differential expression; dopaminergic neuron; experience; flexibility; in vivo; interdisciplinary approach; motivated behavior; motor symptom; mouse genetics; neural; neuropsychiatric disorder; novel; novel strategies; promoter; protocadherin 10; protocadherin 19; psychiatric symptom; response; segregation; 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信号传导与各种精神病和运动症状有关，与DA相关的药物通常使用 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 各种行为，人们相信DA神经元的作用是统一的：发出信号“奖励预测 错误”（RPE），实际上和预测的奖励价值之间的差异。但是，我们和其他人和其他人 表明投射到纹状体不同区域的DA神经元具有不同的特性并服务 不同的功能。我们发现前纹状体（AS），中央和后纹状体（CS/PS）中的DA，以及 纹状体（TS）信号的“尾巴”，规范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的多巴胺能预测必须为 差异和精确地确定了他们适当调节我们的大脑功能。但是，方式 以及在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，我们已经搜索了突触，同质细胞粘附分子，这些分子 在AS，CS/PS和TS中差异表达。我们确定了三种原钙蛋白（PCDH）， PCDH17，PCDH10和PCDH19分别在AS，CS/PS或TS中有选择地表达 发展和成人。此外，在中脑中，da神经元表达了pcdh17、10和19 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-Projecting DA神经元的分子代码 并且它们在建立功能隔离的DA电路中起着关键作用。测试这些想法 我们已经生成了新型的小鼠系，其中CRE在PCDH启动子下表达，并且构成 （null）和有条件的敲除（KO）小鼠的三个PCDH中的每一只。使用这些鼠标线，我们建议 TO：AIM 1：确定PCDH17、10和19是否是功能隔离DA的分子代码 成人的神经元。目标2：研究表达PCDH的DA神经元的灭活和激活的影响 在发展的各个阶段。目标3：检查PCDH蛋白在建立中的作用 特定的DA连接。我们将使用跨学科方法与分子/细胞生物学，组织学， 小鼠遗传，电子显微镜，电生理，体内记录/成像和行为 解决这些目标的技术。我们的工作将分子定义功能上不同的DA电路并揭示 特定的DA电路如何在哺乳动物大脑中建立。 PCDH17/10/19与不同的疾病有关： 情绪障碍和精神分裂症的PCDH17，自闭症和强迫症的PCDH10，以及癫痫和 人格障碍。因此，我们的研究还可以提供特定DA电路与某些疾病之间的联系 并提出新的策略来治疗这些毁灭性疾病。

项目成果

A gradual temporal shift of dopamine responses mirrors the progression of temporal difference error in machine learning.

• DOI: 10.1038/s41593-022-01109-2
• 发表时间: 2022-08
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Amo, Ryunosuke;Matias, Sara;Yamanaka, Akihiro;Tanaka, Kenji F.;Uchida, Naoshige;Watabe-Uchida, Mitsuko
• 通讯作者: Watabe-Uchida, Mitsuko

Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction.

• DOI: 10.1016/j.neuron.2022.08.022
• 发表时间: 2022-11-16
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Akiti, Korleki;Tsutsui-Kimura, Iku;Xie, Yudi;Mathis, Alexander;Markowitz, Jeffrey E.;Anyoha, Rockwell;Datta, Sandeep Robert;Mathis, Mackenzie Weygandt;Uchida, Naoshige;Watabe-Uchida, Mitsuko
• 通讯作者: Watabe-Uchida, Mitsuko