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

项目摘要 选择动作、评估和存储结果以告知未来反应的过程需要基底神经节（BG）和扩展回路，如外侧缰（LHb）。事实上，在多种人类神经系统疾病中观察到扰动的LHb活性，其中动作选择受损。这包括重性抑郁症，其中LHb的活动模式被破坏与抑郁样表型有因果关系。尽管其在行动选择/结果评价中的关键功能，但LHb内特定神经元类型对健康和疾病中这些过程的贡献仍不完全清楚。以前，我们使用全转录组单细胞测序在LHb内定义了遗传上不同的神经元亚型。此外，我们开发了一个变化的2臂强盗行为任务（2ABT），允许在体内的LHb电路动态的操纵和观察。利用这些工具，我们的目标是研究LHb的活动和贡献的行为，需要更新行动选择在不确定的背景下，根据以前的奖励历史。这是我们的首要假设，不同的，遗传定义的LHb神经元亚型编码的动作，结果，或两者差异控制动作选择行为。压力会导致在不确定的情况下决策错误的增加，压力或抑郁症患者在负面结果后表现出学习率下降。压力和焦虑的人也表现出对不确定性的厌恶，选择更确定但利润较低的结果，而不是具有更高整体利润率的不确定结果。压力是抑郁症发展的主要危险因素，并且已知会破坏LHb活动模式。大脑中去甲肾上腺素（NE）信号传导的增加是应激反应的标志，与HPA轴平行激活，有助于心理社会应激的中枢和外周效应。已知NE应激反应在男性和女性之间不同。在LHb中，NE已知有助于唤醒和焦虑状态。此外，我们已经发现LHb神经元亚型中肾上腺素能受体（AR）的差异表达。因此，我们认为LHb是决策过程中压力、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改变的基础。我们将在三个目标中检验这些假设。在目标1A中，我们将确定在2ABT期间，哪些遗传定义的子字段编码动作，结果或两者。通过这种方式，我们将定义LHb对动作选择的贡献。在目的1B中，我们将利用不可预测的慢性轻度应激诱导的快感缺失和2ABT来研究慢性应激如何影响LHb和NE信号在动作选择过程中。最后，在目标2中，我们将检查2ABT期间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，这些目标将阐明的机制，LHb调节行动评估健康和慢性压力下的男性和女性。

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.