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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）：腹侧被盖区（VTA）的多巴胺神经元在学习和动机中起核心作用。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。但是当感官线索预测奖励时，他们反而开始对线索做出反应，而他们对奖励的反应则减弱了。此外，当预测的奖励被省略时，他们的活动会暂时受到抑制。从这些观察中，已经假设多巴胺神经元发出预期和实际奖励之间的差异信号，即，他们计算奖励预测误差（RPE）。然而，多巴胺神经元如何计算RPE仍然是未知的。为了理解这个问题，我们必须知道：（1）当期望奖励时，什么机制抑制了多巴胺神经元对奖励的反应;（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。我们实验室以前的一项研究表明，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的激活。这一结果表明，腹侧被盖区GABA神经元抑制多巴胺神经元的反应，奖励时，预期。在这项提议中，为了在实验上验证这一想法，将对腹侧被盖区GABA神经元的持续活动进行光遗传学操纵，并将在电生理学上研究这种操纵如何影响多巴胺神经元对奖赏的反应。第二，虽然先前的研究表明，丘脑腹侧核（NAc）和腹侧苍白球（VP）提供了大量的抑制性输入到多巴胺神经元，和NAc神经元的项目VP，这些连接在调节多巴胺神经元的活动的确切作用仍然不清楚。在初步实验中，单侧NAc的失活被发现大大降低了多巴胺神经元对奖励预测线索的反应。我们将通过实验来验证这一假设，即从NAc到VP到多巴胺神经元的双突触抑制通路负责产生多巴胺神经元对奖励预测线索的反应。总的来说，该项目的目的是在小鼠中使用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。通过对多巴胺神经元放电进行详细的电路级分析，我们将为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提供一个框架。