Experimental examinations of the mechanisms that generate the responses of midbra

产生中胸反应机制的实验检查

基本信息

批准号：
8558913
负责人：
Naoshige Uchida
金额：
$ 41.34万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Dopamine neurons in the ventral tegmental area (VTA) play central roles in learning and motivation. In tasks involving rewards, they respond in a stereotyped fashion. They are activated by unpredicted rewards. But when a sensory cue predicts reward, they instead start responding to the cue, while their response to reward attenuates. Moreover, when a predicted reward is omitted, their activity is transiently suppressed. From these observations, it has been postulated that dopamine neurons signal discrepancies between expected and actual reward, i.e., they compute the reward prediction error (RPE). However, it remains unknown how dopamine neurons compute RPE. To understand this question, it is important to know (1) what mechanisms suppress dopamine neurons' responses to reward when the reward is expected, and (2) what mechanisms are responsible for generating the response of dopamine neurons to reward-predicting cues. A previous study in our laboratory has shown that VTA GABA neurons exhibit sustained activations during the delay between a reward-predictive cue and reward. This result suggests that VTA GABA neurons suppress dopamine neurons' responses to reward when the reward is expected. In this proposal, to test this idea experimentally, the sustained activity of VTA GABA neurons will be optogenetically manipulated, and how this manipulation affects dopamine neurons' responses to reward will be examined electrophysiologically. Second, although previous studies have shown that the nucleus accumbens (NAc) and the ventral pallidum(VP) provide large numbers of inhibitory inputs to dopamine neurons, and NAc neurons project to VP, the exact roles of these connections in regulating the activity of dopamine neurons remain unclear. In a preliminary experiment, inactivation of unilateral NAc was found to greatly reduce dopamine neurons' responses to reward-predictive cues. We will experimentally test the hypothesis that a disynaptic, inhibitory pathway from NAc to VP to dopamine neurons is responsible in generating dopamine neurons' responses to reward-predictive cues. In total, this project aims to experimentally test the aforementioned specific hypotheses using integrative approaches in mice. Malfunctions of the dopamine system are associated with a variety of pathological conditions including depression, schizophrenia and addiction. By providing a detailed, circuit-level analysis of dopamine neuron firing, we will provide a framework for understanding how the brain learns from rewards, and how this system can be disrupted in disease.

描述（由申请人提供）：腹侧被盖区（VTA）的多巴胺神经元在学习和动机中发挥着核心作用。在涉及奖励的任务中，他们以刻板的方式做出反应。它们被不可预测的奖励所激活。但是，当感官提示预测奖励时，他们就会开始对提示做出反应，而对奖励的反应就会减弱。此外，当预测的奖励被忽略时，他们的活动会暂时受到抑制。根据这些观察，假设多巴胺神经元发出预期奖励与实际奖励之间的差异信号，即它们计算奖励预测误差（RPE）。然而，多巴胺神经元如何计算 RPE 仍然未知。要理解这个问题，重要的是要知道（1）当预期奖励时，什么机制抑制多巴胺神经元对奖励的反应，以及（2）什么机制负责产生多巴胺神经元对奖励预测线索的反应。我们实验室之前的一项研究表明，VTA GABA 神经元在奖励预测线索和奖励之间的延迟期间表现出持续激活。这一结果表明，当预期获得奖励时，VTA GABA 神经元会抑制多巴胺神经元对奖励的反应。在该提案中，为了通过实验测试这一想法，VTA GABA 神经元的持续活动将被光遗传学操纵，并且这种操纵如何影响多巴胺神经元对奖励的反应将通过电生理学进行检查。其次，虽然之前的研究表明伏隔核（NAc）和腹侧苍白球（VP）为多巴胺神经元提供大量抑制性输入，并且NAc神经元投射到VP，但这些连接在调节多巴胺活性中的确切作用神经元仍不清楚。在初步实验中，发现单侧 NAc 失活会大大降低多巴胺神经元对奖励预测线索的反应。我们将通过实验检验以下假设：从 NAc 到 VP 再到多巴胺神经元的双突触抑制途径负责产生多巴胺神经元对奖赏预测线索的反应。总的来说，该项目旨在使用小鼠身上的综合方法对上述特定假设进行实验测试。多巴胺系统的功能障碍与多种病理状况有关，包括抑郁症、精神分裂症和成瘾症。通过对多巴胺神经元放电进行详细的电路级分析，我们将提供一个框架来理解大脑如何从奖励中学习，以及该系统如何在疾病中被破坏。