Determining the role of the primate raphe-habenula circuit in multi-attribute decision-making

确定灵长类动物中缝-缰核回路在多属性决策中的作用

• 批准号: 10464321
• 负责人: Yan-Yang Feng
• 金额: $ 5.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464321
• 关键词: Adaptive Behaviors; Address; Animal Model; Animals; Antidepressive Agents; Anxiety; Basal Ganglia; Behavioral; Brain; Cell Nucleus; Choice Behavior; Complex; Data; Decision Making; Disease; Dorsal; Electric Stimulation; Evaluation; Future; GABA Agonists; Globus Pallidus; Habenula; Human; Individual; Injections; Investigation; Lateral; Mediating; Mental Depression; Mental Health; Monkeys; Neuromodulator; Neurons; Outcome; Output; Pharmacologic Substance; Play; Primates; Procedures; Process; Psychiatrist; Psychopathology; Research; Rewards; Risk; Role; Serotonin; Signal Transduction; Source; Specificity; Structure; System; Testing; Therapeutic Effect; Time; Training; Work; anxiety-like behavior; anxiety-related disorders; base; depressive symptoms; design; discount; dorsal raphe nucleus; experimental study; insight; news; novel therapeutics; optogenetics; preference; raphe nuclei; relating to nervous system; response; skills

Value-based decision-making, driven by each individual’s own appraisal of available offers, is an indispensable part of our lives and a key determinant of mental health. Internalizing disorders (e.g. depression, anxiety), commonly feature maladaptive decision-making characterized by the assignment of erroneously low value to rewarding activities and objects. Elucidating the neural basis of value-based decision-making is thus crucial for understanding adaptive behavior and may provide translational insights. The lateral habenula (LHb) is thought to act as the brain’s “bad news” center by broadcasting signals that decrease the value of rewards and is implicated in depressive and anxiety-like behaviors. Moreover, LHb is known to receive strong inputs from the raphe nuclei, the brain’s source of serotonin, a neuromodulator that is the target of most pharmaceuticals for internalizing disorders and many other psychopathologies. The dorsal raphe (DR), the largest serotonergic nucleus, is known to be involved in value-related processes, though the role of its inputs to LHb is unclear. In particular, despite its potential importance, little is known about how the primate raphe-LHb circuit mediates the complex strategies we use every day to choose activities and objects, a decision-making process which requires integration across many reward attributes, such as amount, risk, and delay. We hypothesize that LHb plays a central role in integrating attributes in order to compute the value of offers and guide decisions online, using delay-related signals from DR to discount value. Aim 1 investigates the role of LHb in multi-attribute decision-making. LHb signals are proposed to reflect preference integrated across the many attributes that may define a reward and are ultimately broadcast to cortex and the basal ganglia, regions with a prominent role in selecting actions. Preliminary data suggest that neurons in LHb integrate reward attributes in a manner consistent with negative subjective value and that increasing LHb firing with weak electrical stimulation during an offer’s presentation biases choice away from that offer in a manner consistent with decreased offer value. Aim 2 investigates the role of DR multi-attribute decision-making. DR is proposed to signal variables related to time delays until reward. If this is true in the context of decision-making, DR could send delay and related attributes to LHb to guide decisions. Disruptions in this circuit could then interfere with evaluation and choice of multi-attribute offers, and amelioration of such disruptions by antidepressants could contribute to their therapeutic effects. Subsequent experiments will test the hypothesis that the sensitivity of LHb and choice preference to reward delay is controlled by DR. These Aims will clarify the role of the primate raphe-LHb circuit in multi-attribute decision-making, laying the groundwork for my future investigations of the behavioral and neural systems that underlie internalizing and related disorders and undoubtedly opening the door to new therapeutic avenues. Through these Aims, I will acquire the skills needed to successfully drive this research as I develop into an independent psychiatrist-neuroscientist.

由每个人自己对可用优惠的评估驱动的基于价值的决策是必不可少的 我们生活的一部分，是心理健康的关键决定者。间隔疾病（例如抑郁症，动画）， 通常特征是适应不良的决策，其特征是分配错误的低值 奖励活动和物体。因此，阐明基于价值决策的神经基础对于 了解适应性行为，并可能提供翻译见解。人们认为外侧Habenula（LHB） 通过广播信号来降低奖励的价值，是大脑的“坏消息”中心 以抑郁和类似焦虑的行为实施。此外，已知LHB从 Raphe核，大脑的血清素来源，一种神经调节剂，是大多数药物的靶标 内部疾病和许多其他心理病理学。背侧raphe（DR），最大的血清能 已知核与价值相关的过程涉及，尽管其输入对LHB的作用尚不清楚。 特别是目的地的潜在重要性，关于灵长类动物Raphe-LHB电路如何介导 我们每天使用的复杂策略选择活动和对象，这是一个决策过程 需要在许多奖励属性（例如数量，风险和延迟）上集成。我们假设这一点 LHB在整合属性中起着核心作用，以计算要约的价值和指南 在线决策，使用与DR的延迟相关信号到折扣价值。 AIM 1调查了 LHB在多属性决策中。提出了LHB信号以反映整合的偏好 许多可能定义奖励的属性，并最终向皮质和基底神经节广播 在选择动作方面发挥着重要作用。初步数据表明LHB中的神经元综合奖励 属性以与负主观价值一致的方式以及汗水增加LHB发射的属性 要约期间的电刺激以一致的方式远离该报价的选择 降低要约价值。 AIM 2研究了多属性决策的作用。提出了博士 发出与时间延迟有关的变量，直到奖励。如果在决策的背景下是正确的，博士可以 向LHB发送延迟和相关属性以指导决策。然后，该电路中的破坏可能会干扰 评估和选择多属性优惠，以及抗抑郁药对这种干扰的改善可以 有助于他们的治疗作用。随后的实验将检验以下假设。 LHB和选择偏爱奖励延迟由DR控制。这些目标将阐明隐私的作用 Raphe-lhb电路在多属性决策中，为我对未来的调查奠定了基础 行为和神经系统的内在化和相关疾病的基础，无疑开放 通向新的治疗途径的门。通过这些目标，我将获得成功推动这一点所需的技能 随着我发展成为独立的精神科医生 - 神经科学家的研究。