Neural circuits that regulate dopamine neuron activity

描述（由申请人提供）：中脑多巴胺系统对学习，动机和处理奖励至关重要。该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。多巴胺神经元位于腹侧被盖区（VTA）和黑质致密部（SNc），被认为是传播奖励预测误差（RPE）信号，即实际奖励和预期奖励之间的差异。此外，最近的研究表明，VTA和SNc中的多巴胺神经元分别传递不同的信号、价值和显著性。虽然这些观察引起了极大的兴趣，但多巴胺神经元如何计算错误信号尚不清楚。本项目将解决以下两个主要问题：(1)多巴胺神经元如何计算RPE信号？(2) VTA和SNc多巴胺神经元不同反应特性的原因是什么？尽管VTA和SN的局部gaba能神经元对多巴胺神经元有强大的影响，但对其在行为背景下的放电模式知之甚少。具体目标1将验证这些gaba能神经元编码奖励期望的假设，这有助于多巴胺神经元的预测误差计算。为了验证这一假设，当小鼠执行经典条件反射范式时，VTA的峰值活动将被记录下来，在这种范式中，它们将不同的气味与不同的结果（大水、小水、无气味和喷气）联系起来。为了确定所记录神经元的神经递质类型，多巴胺能或gaba能神经元将被通道视紫红质（ChR2）标记，并检查所记录的神经元是否对光有反应。首先，确定的多巴胺神经元是否确实传递RPE信号将被检查。其次，VTA gaba能神经元是否在奖励预测气味和奖励传递之间的延迟期间表现出反映即将到来的奖励值的持续激活将被测试。特异性目的2将测试多巴胺神经元在不同条件下的奖励反应是否可以用VTA gaba能神经元的反应谱来解释。当小鼠将新的气味与奖励联系在一起，或者在控制奖励时间的任务中，将记录下VTA中多巴胺能和gaba能神经元的活动。特异性目的3将验证局部gaba能神经元的活动可以解释VTA和黑质（SN）中多巴胺神经元的不同反应特性的假设。具体来说，SN GABAergic神经元信号预测厌恶和奖励事件的假设将被测试。总的来说，在拟议的项目中获得的结果将阐明对多巴胺神经元的RPE计算做出贡献的关键参与者。了解RPE计算的详细神经回路机制将有助于我们理解抑郁症、精神分裂症的病因

DESCRIPTION (provided by applicant): The midbrain dopamine system is critical for learning, motivation and processing rewards. Malfunctions of this system are associated with a variety of pathological conditions including depression, schizophrenia and addiction. Dopamine neurons, located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), are thought to broadcast reward prediction error (RPE) signals, i.e., the discrepancy between actual reward and expected reward. Furthermore, recent studies have indicated that dopamine neurons in the VTA and SNc convey different signals, value and saliency, respectively. While these observations have generated great interest, how dopamine neurons compute error signals is unknown. This project will address the following two main questions: (1) How do dopamine neurons compute RPE signals? and (2) What underlies the different response properties of VTA and SNc dopamine neurons? Although local GABAergic neurons in VTA and SN exert a powerful influence on dopamine neurons, little is known about their firing patterns in a behavioral context. Specific Aim 1 will test the hypothesis that these GABAergic neurons encode reward expectation, which contributes to the prediction error calculations of dopamine neurons. To test this hypothesis, the spiking activity from VTA will be recorded while mice perform a classical conditioning paradigm in which they associate different odors with different outcomes (big water, small water, nothing and airpuff). To identify neurotransmitter types of recorded neurons, dopaminergic or GABAergic neurons will be tagged with channelrhodopsin (ChR2) and whether recorded neurons respond to light will be examined. First, whether identified dopamine neurons indeed convey RPE signals will be examined. Second, whether VTA GABAergic neurons show sustained activation reflecting upcoming reward value during the delay between a reward- predicting odor and the delivery of reward will be tested. Specific Aim 2 will test whether the reward responses of dopamine neurons under various conditions can be accounted for by the response profiles of VTA GABAergic neurons. The activity of dopaminergic and GABAergic neurons in VTA will be recorded while mice associate new odors with reward, or in a task in which the timing of reward was manipulated. Specific Aim 3 will test the hypothesis that the activity of local GABAergic neurons can explain the different response properties of dopamine neurons in the VTA and substantia nigra (SN). Specifically, the hypothesis that SN GABAergic neurons signal the prediction of aversive as well as rewarding events will be tested. In total, the results obtained in the proposed project will elucidate the key players contributing o RPE calculations of dopamine neurons. Understanding the detailed neural circuit mechanisms for RPE computation will facilitate our ability to understand etiology of depression, schizophrenia and addiction, and to design preventive and therapeutic approaches for these disorders.