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.

项目摘要 多巴胺神经元（DN）是动机性行为的关键调节因子，而多巴胺神经元的缺陷 信号传导可能是一些精神疾病的基础，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。这一领域的大部分工作都是基于 根据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，包括我们在内的几个小组的工作表明，投射到不同方向的DN 靶显示出不同的性质并提供不同的功能。在这项建议中，我们的目的是将 DN的多样性由其连接性和与其功能的活动性定义。 最近的一个例子，从我们的工作中得出，是神经元投射到纹状体的后部“尾巴”， (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，信号“典型”RPE，被奖励激活，被负抑制。 事件相比之下，TS投射DN被新的刺激和一部分负性刺激激活。 事件 在这里，基于我们的初步结果，我们将比较VS和TS投射DN的（1） 活动，（2）行为过程中的功能，（3）活动产生的机制。 我们将测试主要假设，即TS投射DN集成了一组独特的输入，信号威胁 预测错误，并积极加强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射的DN的活动。具体目标2将 证明投射特异性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 以一种特定于项目的方式对DN的模式进行分析。如果我们的主要假设成立， 证明VS和TS中的多巴胺在算法层面上以类似的方式运作： 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（结果值或威胁）。的方法和结果 这项研究将为将来研究其他糖尿病肾病人群铺平道路。这将进一步 目的是阐明一个统一的理论，关于计算算法，多个DN 人口功能。我们希望这些结果能为多巴胺能缺陷提供见解， 脑疾病中的多巴胺定向治疗干预。