Experimental examinations of the mechanisms that generate the responses of midbra

描述(由申请人提供)：腹侧被盖区(VTA)中的多巴胺神经元在学习和动机中发挥核心作用。在涉及奖励的任务中，他们会以刻板印象的方式做出反应。它们被意想不到的回报激活。但当感觉提示预测奖励时，它们反而开始对提示做出反应，而它们对奖励的反应减弱。此外，当预测的奖励被省略时，它们的活动会暂时受到抑制。从这些观察中可以推测，多巴胺神经元发出预期奖赏与实际奖赏之间存在差异的信号，即它们计算奖赏预测误差(RPE)。然而，目前尚不清楚多巴胺神经元是如何计算RPE的。要理解这个问题，重要的是要知道(1)当预期奖赏时，是什么机制抑制了多巴胺神经元对奖赏的反应，以及(2)什么机制负责产生多巴胺神经元对奖赏预测线索的反应。我们实验室以前的一项研究表明，在奖赏预测提示和奖赏之间的延迟期间，VTA GABA神经元表现出持续的激活。这一结果表明，VTA GABA神经元抑制了多巴胺神经元对预期奖赏的反应。在这项提议中，为了从实验上验证这一想法，将对VTA GABA神经元的持续活动进行光基因操作，并从电生理学角度检查这种操作如何影响多巴胺神经元对奖赏的反应。第二，虽然以前的研究表明伏核(NAC)和腹侧苍白球(VP)为多巴胺神经元提供大量的抑制性输入，而NAC神经元投射到VP，但这些联系在调节多巴胺神经元活动中的确切作用尚不清楚。在初步实验中，单侧NAC的失活被发现极大地降低了多巴胺神经元对奖励预测线索的反应。我们将从实验上测试这一假设，即从NAC到VP再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赏预测线索的反应。总而言之，该项目的目的是在小鼠身上使用综合方法对上述特定假设进行实验测试。多巴胺系统的故障与包括抑郁症、精神分裂症和成瘾在内的各种病理状况有关。通过提供多巴胺神经元放电的详细的电路水平分析，我们将提供一个框架，以了解大脑如何从奖励中学习，以及这个系统如何在疾病中被破坏。

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.