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：
9247804
负责人：
Naoshige Uchida
金额：
$ 41.83万
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 2018-03-31
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）：腹侧盖区域（VTA）中的多巴胺神经元在学习和动机中起着核心作用。在涉及奖励的任务中，他们以刻板印象的方式做出回应。他们被无预料的奖励激活。但是，当感官提示预测奖励时，他们开始对提示做出回应，而他们对奖励减弱的反应。此外，当省略预测的奖励时，他们的活动将被暂时抑制。从这些观察结果中，已经假设多巴胺神经元在预期和实际奖励之间信号差异，即它们计算奖励预测误差（RPE）。但是，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，哪些机制抑制了多巴胺神经元对奖励的反应，以及（2）哪些机制负责产生多巴胺神经元以奖励预测提示。我们实验室的先前一项研究表明，VTA GABA神经元在奖励预测的提示和奖励之间表现出持续的激活。该结果表明，VTA GABA神经元在预期奖励时抑制了多巴胺神经元对奖励的反应。在该建议中，为了通过实验测试这一想法，将通过光遗传操纵VTA GABA神经元的持续活性，以及该操作如何影响多巴胺神经元对奖励的反应，将在电生理上进行检查。其次，尽管先前的研究表明，伏隔核（NAC）和腹侧颗粒（VP）为多巴胺神经元提供了大量的抑制性输入，而NAC神经元投入了VP，但这些连接在调节多巴胺神经元活性方面的确切作用仍然没有。在初步实验中，发现单侧NAC的失活可大大减少多巴胺神经元对奖励预测性提示的反应。我们将通过实验检验以下假设：从NAC到VP到多巴胺神经元的抑制性途径是产生多巴胺神经元对奖励预测性提示的反应的原因。总体而言，该项目旨在使用小鼠中的综合方法在实验中测试上述特定假设。多巴胺系统的故障与多种病理状况有关，包括抑郁症，精神分裂症和成瘾。通过提供多巴胺神经元射击的详细的电路级分析，我们将提供一个框架，以了解大脑如何从奖励中学习，以及如何在疾病中破坏该系统。