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

项目摘要 多巴胺神经元是动机行为的关键调节者，也是多巴胺的缺陷。 信号可能是一些精神障碍的基础，包括成瘾、抑郁和精神分裂症， 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 关于域名编码奖励预测误差(RPE)的教条以及它们以统一的方式这样做 举止。然而，包括我们在内的几个小组的工作表明，DNS投射到不同的 目标表现出不同的属性和服务不同的功能。在这项建议中，我们的目标是将 由其与其功能的连接性和活跃性所定义的域名的多样性。 从我们的工作中得出的一个最近的例子是，dns投射到纹状体的后部“尾部”。 (TS)在许多方面与向腹侧纹状体(VS)和其他区域投射的DNS不同。VS- 投射的核糖体蛋白被奖赏所激活，而被负性所抑制。 事件。相反，新的刺激和负性刺激的子集激活了TS-投射神经元 事件。 在这里，基于我们的初始结果，我们将比较VS-和TS-Projecting的DN关于它们的(1) 活动，(2)在行为中起作用，(3)活动产生的机制。 我们将测试主要假设，即TS投射的域名集成了一组唯一的输入，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 将表征特定于投影的域名在行为过程中的活动。特定目标2将 演示特定于投影的域名的功能和活动模式之间的因果联系。 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进行的域名系统模式。如果我们的主要假设成立，结果将是 证明VS和TS中的多巴胺在算法水平上以类似的方式运作：在 在这两个系统中，多巴胺的增加都会导致某些行为的易化(接近或 避免)或基于刺激的预测(对结果价值或威胁)。研究方法和结果 这项拟议的研究将为未来研究其他糖尿病肾病人群铺平道路。这将进一步 目的是阐明关于计算算法的统一理论，通过该算法，多个DN 人口功能发挥作用。我们希望这些结果能提供对多巴胺能缺陷的洞察，甚至 脑部疾病的多巴胺指导的治疗干预。

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.