Functional role of tachykinin 1-expressing lateral habenula neurons in flexible reward-guided behavior

项目摘要 跨物种的生存取决于动物转换正在进行的行为以优化目标的能力，例如 在动态环境中获得奖励。这种基于变化的行为适应过程 环境突发事件，通常被称为行为灵活性，在许多方面受到损害， 神经精神障碍，包括抑郁症、精神分裂症和强迫症。一个关键 自适应奖励计算的元素是反映差异的奖励预测误差（RPE）信号 获得的奖励和预期的奖励之间的关系。外侧缰核（LHb）在信号传导中起着公认的作用 RPE，最近更广泛地涉及调整选择行为，以应对 奖励意外事件这表明LHb作为疾病治疗干预的潜在靶点 以不灵活的行为为特点。然而，LHb也参与了各种各样的情绪和 动机行为，包括压力、恐惧、厌恶、攻击以及社会和父母行为。因此，我们认为， 开发治疗方法，使行为灵活性，而不冒一系列副作用的风险，首先需要确定 特定的LHb亚群潜在的灵活的行为。 在这个建议中，我们使用细胞类型特异性的方法来监测和操纵一个遗传定义的神经元。 亚群发现优先信号RPE，以确定如何LHb RPE信号促进灵活的行为。 在我们的第一个目标中，我们将确定用于编码奖励预测错误的神经元编码机制， LHb。在我们的第二个目标中，我们将确定这些信号如何有助于灵活的奖励导向决策。 这些实验将揭示LHb RPE信号在灵活行为中的功能作用， 提供了对潜在靶点的更精确的了解，用于定制治疗以不灵活为特征的疾病 行为

PROJECT SUMMARY Survival across species hinges on an animal’s ability to switch ongoing behaviors to optimize goals, such as obtaining rewards, in dynamic environments. This process of adapting behaviors based on changes in environmental contingencies, commonly referred to as behavioral flexibility, is impaired across many neuropsychiatric disorders including depression, schizophrenia, and obsessive-compulsive disorder. A key element of adaptive reward computations is reward prediction error (RPE) signals, which reflect the discrepancy between obtained and expected rewards. The lateral habenula (LHb) plays a well-established role in signaling RPE and has recently been more broadly implicated in adjusting choice behavior in response to changes in reward contingencies. This suggests the LHb as a potential target for therapeutic intervention for diseases characterized by inflexible behavior. However, the LHb is also involved in a diverse range of emotional and motivational behaviors including stress, fear, aversion, aggression, and social and parental behavior. Therefore, developing treatments that behavioral flexibility without risking a cascade of side effects first requires identifying specific LHb subpopulations underlying flexible behavior. In this proposal, we use cell-type-specific approaches to monitor and manipulate a genetically-defined neuronal subpopulation found to preferentially signal RPE to determine how LHb RPE signals facilitate flexible behavior. In our first aim, we will identify the neuronal coding mechanism used to encode reward prediction error in the LHb. In our second aim, we will determine how these signals contribute to flexible reward-guided decision making. Together these experiments will reveal the functional role of LHb RPE signaling in flexible behavior, which will provide more refined insight into potential targets for tailored treatment of disorders characterized by inflexible behavior.