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）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，他们的反应是刻板的。它们会被意想不到的奖励激活。但当感官提示预示着奖励时，它们反而开始对提示做出反应，而对奖励的反应却减弱了。此外，当预测的奖励被忽略时，它们的活动会暂时受到抑制。根据这些观察，我们假设多巴胺神经元在预期奖励和实际奖励之间发出信号差异，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。为了理解这个问题，有必要了解(1)当预期得到奖励时，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神经元在奖励预测提示和奖励之间的延迟期间表现出持续的激活。这一结果表明VTA GABA神经元在预期奖励时抑制多巴胺神经元对奖励的反应。在本研究中，为了在实验上验证这一观点，我们将对VTA - GABA神经元的持续活动进行光遗传学操作，并对这种操作如何影响多巴胺神经元对奖励的反应进行电生理学研究。其次，尽管已有研究表明伏隔核（NAc）和腹侧白质（VP）向多巴胺神经元提供大量抑制输入，且NAc神经元向VP投射，但这些连接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，发现单侧NAc的失活大大降低了多巴胺神经元对奖励预测线索的反应。我们将通过实验验证这一假设，即从NAc到VP再到多巴胺神经元的失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。总而言之，本项目旨在通过实验验证上述特定假设在小鼠中使用综合方法。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回路级分析，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。

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.