The diversity of dopamine neurons: from connectivity and activity to functions.

多巴胺神经元的多样性：从连接性和活动到功能。

• 批准号: 9791016
• 负责人: Naoshige Uchida
• 金额: $ 53.67万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791016
• 关键词: Algorithms; Area; Axon; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain Diseases; Calcium; Choice Behavior; Computational algorithm; Corpus striatum structure; Cues; Defect; Disease; Dopamine; Eating Disorders; Electrophysiology (science); Event; Exhibits; Fiber; Future; Generations; Goals; Head; Image; Link; Loudness; Measures; Mental Depression; Mental disorders; Methods; Midbrain structure; Monitor; Mus; Neurons; Nose; Outcome; Output; Parkinson Disease; Pathologic; Pattern; Photometry; Population; Property; Psychological reinforcement; Rabies virus; Rewards; Role; Schizophrenia; Sensory; Signal Transduction; Stimulus; System; Tail; Taste Perception; Testing; Therapeutic Intervention; Time; Ventral Striatum; Work; addiction; avoidance behavior; base; cell type; classical conditioning; dopamine system; dopaminergic neuron; expectation; insight; motivated behavior; nervous system disorder; neural circuit; novel; optogenetics; presynaptic neurons; response; sound; theories

Project Summary Dopamine neurons (DNs) are key regulators of motivated behaviors, and defects in dopamine signaling may underlie some psychiatric disorders including addiction, depression, and schizophrenia, as well as neurological disorders such as Parkinson's. Much of the work in this area has been based on the dogma that DNs encode reward prediction errors (RPE) and that they do so in a uniform manner. However, work from several groups, including ours, indicates that DNs projecting to different targets exhibit distinct properties and serve distinct functions. In this proposal, we aim to link the diversity of DNs defined by their connectivity and activity with their functions. One recent example, drawn from our work, is that DNs projecting to the posterior `tail' of the striatum (TS) differ in many ways from DNs projecting to the ventral striatum (VS) and other regions. VS- projecting DNs, which signal `canonical' RPEs, are activated by reward and inhibited by negative events. By contrast, TS-projecting DNs are activated by novel stimuli and a subset of negative events. Here, based on our initial results, we will compare VS- and TS-projecting DNs with regard to their (1) activity, (2) function during behaviors, and (3) mechanism underlying the generation of the activities. We will test the main hypothesis that TS-projecting DNs integrate a unique set of inputs, signal threat prediction errors, and positively reinforces threat predictions or avoidance behaviors. Specific Aim 1 will characterize the activity of projection-specific DNs during behavior. Specific Aim 2 will demonstrate the causal link between the function and the activity patterns of projection-specific DNs. Specific Aim 3 will aim to understanding neural circuit mechanisms that generate distinct response patterns of DNs in a projection-specific manner. If our main hypothesis holds true, the results will demonstrate that dopamine in VS and TS operates in a similar manner at the algorithmic level: in both systems, an increase in dopamine results in facilitation of certain behaviors (approach or avoidance) or stimulus-based predictions (of outcome value or a threat). The methods and results of the proposed study will pave the way for looking at other DN populations in the future. This will further the goal of elucidating a unifying theory regarding the computational algorithm by which multiple DN populations function. We expect these results to provide insights into dopaminergic defects and even dopamine-directed therapeutic interventions in brain disorders.

项目概要 多巴胺神经元 (DN) 是动机行为和多巴胺缺陷的关键调节器 信号传导可能是某些精神疾病的基础，包括成瘾、抑郁症和精神分裂症， 以及帕金森氏症等神经系统疾病。该领域的大部分工作都是基于 DN 编码奖励预测错误 (RPE) 的教条，并且它们以统一的方式进行编码 方式。然而，包括我们在内的多个小组的工作表明，DN 投射到不同的 目标表现出不同的属性并发挥不同的功能。在本提案中，我们的目标是将 DN 的多样性由其功能的连接性和活动性定义。 我们最近的工作中得出的一个例子是，DN 投射到纹状体的后“尾部” (TS) 在许多方面与投射到腹侧纹状体 (VS) 和其他区域的 DN 不同。 VS- 投射 DN 是“规范”RPE 的信号，被奖励激活并被负性抑制 事件。相比之下，TS 投射 DN 会被新的刺激和负性刺激的子集激活。 事件。 在这里，根据我们的初步结果，我们将比较 VS 和 TS 投影 DN 的 (1) 活动，（2）行为期间的功能，以及（3）活动生成的机制。 我们将测试主要假设，即 TS 投影 DN 集成了一组独特的输入、信号威胁 预测错误，并积极强化威胁预测或回避行为。具体目标 1 将表征行为期间特定于投影的 DN 的活动。具体目标 2 将 证明投影特定 DN 的功能和活动模式之间的因果关系。 具体目标 3 旨在了解产生不同反应的神经回路机制 以特定于投影的方式形成 DN 模式。如果我们的主要假设成立，结果将 证明 VS 和 TS 中的多巴胺在算法层面以类似的方式运作： 在这两个系统中，多巴胺的增加会促进某些行为（接近或 回避）或基于刺激的预测（结果价值或威胁）。方法和结果 拟议的研究将为未来研究其他 DN 人群铺平道路。这将进一步 目标是阐明关于多个 DN 的计算算法的统一理论 人口功能。我们希望这些结果能够深入了解多巴胺能缺陷，甚至 以多巴胺为导向的脑部疾病治疗干预。