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。这一系统的故障与各种病理状况有关，包括抑郁症、精神分裂症和成瘾。位于腹侧被盖区（VTA）和黑质旁核（SNc）的多巴胺神经元被认为传播奖励预测错误（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，腹侧被盖区和黑质腹侧核的多巴胺神经元分别传递不同的信号、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）腹侧被盖区和黑质腹侧被盖区多巴胺神经元的不同反应特性的基础是什么？虽然VTA和SN中的局部GABA能神经元对多巴胺神经元产生强大的影响，但对它们在行为背景下的放电模式知之甚少。具体目标1将测试这些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。为了测试这一假设，将记录来自VTA的尖峰活动，同时小鼠执行经典的条件反射范例，其中它们将不同的气味与不同的结果（大水、小水、空无和喷气）相关联。为了鉴定记录的神经元的神经递质类型，将用通道视紫红质（ChR2）标记多巴胺能或GABA能神经元，并检查记录的神经元是否对光响应。首先，将检查所识别的多巴胺神经元是否确实传递RPE信号。第二，将测试VTA GABA能神经元是否在奖励预测气味和奖励递送之间的延迟期间显示反映即将到来的奖励值的持续激活。具体目标2将测试在各种条件下多巴胺神经元的奖赏反应是否可以通过腹侧被盖区GABA能神经元的反应谱来解释。当小鼠将新气味与奖励联系起来时，或在操纵奖励时间的任务中，将记录腹侧被盖区中多巴胺能和GABA能神经元的活动。具体目标3将检验以下假设：局部GABA能神经元的活动可以解释腹侧被盖区和黑质（SN）中多巴胺神经元的不同反应特性。具体而言，将测试SN GABA能神经元发出厌恶和奖励事件的预测信号的假设。总之，在拟议的项目中获得的结果将阐明多巴胺神经元的RPE计算的关键球员。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、 和成瘾，并为这些疾病设计预防和治疗方法。 公共卫生相关性：中脑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。了解调节多巴胺神经元的神经回路将加深我们对这些疾病病因的理解，并有助于预防和治疗方法的设计。

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. PUBLIC HEALTH RELEVANCE: Malfunction of the midbrain dopamine system is associated with a variety of pathological conditions including depression, schizophrenia and addiction. Understanding neural circuits that regulate dopamine neurons will deepen our understanding of the etiology of these diseases and aid in the design of preventive and therapeutic approaches.