NE contributions to Lateral habenula control of action evaluation under chronic stress

项目摘要 选择动作、评估和存储结果以通知未来反应的过程需要基底节(BG)和扩展环路，如外侧缰核(LHb)。事实上，在动作选择受损的多种人类神经疾病中，都观察到LHb活性受扰。这包括严重的抑郁症，其中LHb的活动模式中断与抑郁样表型有因果关系。尽管LHb在行为选择/结果评估中具有关键作用，但LHb内特定神经元类型在健康和疾病中对这些过程的贡献仍不完全清楚。之前，我们使用全转录组单细胞测序定义了LHb内遗传上不同的神经元亚型。此外，我们开发了一种双臂强盗行为任务(2ABT)的变体，允许在体内操纵和观察LHb电路动力学。利用这些工具，我们的目标是研究LHB的活动和对需要基于以前的奖励历史更新不确定上下文中的动作选择的行为的贡献。我们的主要假设是，不同的、基因定义的LHb神经元亚型编码动作、结果或两者，以不同的方式控制动作选择行为。压力会导致在不确定的环境中做出决策的错误增加，压力或抑郁的患者在出现负面结果后表现出学习速度的下降。紧张和焦虑的人也表现出对不确定性的厌恶，他们选择了更确定但利润更低的结果，而不是总体盈利能力更高的不确定结果。压力是抑郁障碍发展的一个主要风险因素，众所周知，它会扰乱LHb的活动模式。大脑中去甲肾上腺素(NE)信号的增加是应激反应的一个标志，它与HPA轴平行激活，促成了心理社会应激的中枢和外周效应。众所周知，男性和女性的应激反应是不同的。在LHb，NE被认为对唤醒和焦虑状态都有贡献。此外，我们还发现肾上腺素能受体(AR)在LHb神经元亚型中有不同的表达。因此，我们推测LHb在决策过程中是压力、焦虑和抑郁障碍相互作用的中心。我们进一步假设，LHb神经元亚型的扰动活动是应激诱导的动作选择变化的基础。我们将通过三个目标来检验这些假设。在目标1A中，我们将确定在2ABT期间哪些遗传定义的子域编码动作、结果或两者。通过这种方式，我们将定义LHb对行动选择的贡献。在目标1B中，我们将利用不可预测的慢性轻度应激引起的快感丧失和2ABT来研究慢性应激在动作选择过程中如何影响LHb和NE信号。最后，在目标2中，我们将在2ABT期间检查LHb中的特定AR。在2ABT任务中，我们预测负性结果的学习将由LHb中的NE信号编码。总之，这些目的将阐明LHb调节男性和女性在健康和慢性应激下的行为评估的机制。

Project Summary The process of selecting an action, evaluating, and storing the outcome to inform future responses requires the basal ganglia (BG) and extended circuits such as the lateral habenula (LHb). Indeed, perturbed LHb activity is observed in multiple human neurological disorders where action selection is impaired. This includes major depressive disorders where disrupted activity patterns in the LHb are causally related to depression-like phenotypes. Despite its critical function in action selection/outcome evaluation, the contributions of specific neuron types within the LHb to these processes in both health and disease remain incompletely understood. Previously, we defined genetically distinct neuronal subtypes within the LHb using whole transcriptome single-cell sequencing. Further, we developed a variation of a 2-armed bandit behavioral task (2ABT) that allows for manipulation and observation of LHb circuit dynamics in vivo. Utilizing these tools, we aim to study LHb activity and contribution to a behavior that requires updating action selection in uncertain contexts based on previous reward history. It is our overarching hypothesis that distinct, genetically defined LHb neuronal subtypes encode the action, the outcome, or both to differentially control action selection behavior. Stress leads to increased errors in decision making in uncertain contexts and stress or depressed patients show decreased learning rates following negative outcomes. Stressed and anxious individuals also show aversion to uncertainty, selecting more certain but less profitable outcomes rather than uncertain outcomes with higher overall profitability. Stress is a major risk factor for depressive disorder development and is known to disrupt LHb activity patterns. Increased norepinephrine (NE) signaling in the brain is a hallmark of stress response, activating in parallel with the HPA-axis contributing to both central and peripheral effects of psychosocial stress. NE stress response is known to differ between males and females. In the LHb, NE is known to contribute to states of both arousal and anxiety. Additionally, we have found differential expression of adrenergic receptors (ARs) in LHb neuronal subtypes. Consequently, we surmise LHb serves as a hub for the interaction of stress, anxiety and depressive disorders during decision making. We further hypothesize that perturbed activity in LHb neuronal subtypes underlie stress induced alterations in action selection. We will examine these hypotheses in 3 aims. In Aim 1A we will determine which genetically defined subfields encode the action, the outcome, or both during a 2ABT. In this way we will define LHb contributions to action selection. In Aim 1B we will utilize the unpredictable chronic mild stress induced anhedonia and the 2ABT to examine how chronic stress affects LHb and NE signaling during action selection. Finally in Aim 2 we will examine specific ARs in the LHb during the 2ABT. During 2ABT tasks, we predict learning of negative outcomes will be encoded by NE signaling in the LHb. Together, these aims will elucidate the mechanism by which the LHb modulates action evaluation in health and under chronic stress in male and females.