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

基于价值的决策是不可或缺的，这种决策是由每个人自己对可提供的报价的评估驱动的 这是我们生活的一部分，也是心理健康的关键决定因素。内化性障碍(如抑郁、焦虑)， 通常以不适应决策为特征，其特征是将错误的低值分配给 奖励活动和对象。因此，阐明基于价值的决策的神经基础对于 理解适应性行为，并可能提供翻译洞察。认为外侧缰核(LHb) 充当大脑的“坏消息”中心，通过传播信号来降低奖励的价值，并 牵涉到抑郁和类似焦虑的行为。此外，众所周知，LHb从 中缝核团是大脑5-羟色胺的来源，是一种神经调节剂，是大多数药物治疗的靶点 内在化障碍和许多其他精神病态。最大的5-羟色胺能神经元--中缝背核 尽管其对LHb的输入作用尚不清楚，但已知其参与了与价值相关的过程。在……里面 特别是，尽管它具有潜在的重要性，但人们对灵长类中缝-LHb回路如何调节 我们每天使用复杂的策略来选择活动和对象，这是一个决策过程， 需要集成多个奖励属性，如金额、风险和延迟。我们假设 LHB在整合属性以计算报价和指导价值方面发挥着核心作用 在线决策，使用从DR到折扣值的延迟相关信号。目标1调查了 LHB在多属性决策中的应用建议使用LHB信号来反映在整个 许多属性可以定义奖励，并最终传播到皮质和基底节、区域 在选择行动方面具有突出的作用。初步数据表明，LHb中的神经元整合了奖赏 属性以与负主观值一致的方式，并增加LHb激发与弱 在报价陈述期间的电刺激以一致的方式使选择偏离该报价 出价价值下降。目的2研究灾难恢复多属性决策的作用。建议使用DR 以信号通知与时间延迟相关的变量，直到奖励。如果这在决策的背景下是正确的，那么Dr 向LHb发送延迟和相关属性以指导决策。此电路中的中断可能会干扰 多属性报价的评估和选择，以及抗抑郁药物对这种干扰的改善可能 有助于它们的治疗效果。随后的实验将检验这一假设，即 LHB和对奖赏延迟的选择偏好由Dr.控制，这些目标将阐明灵长类的作用 RAPHE-LHb回路中的多属性决策，为我今后的研究奠定了基础 行为和神经系统是内化和相关障碍的基础，无疑打开了 通往新的治疗途径的大门。通过这些目标，我将获得成功推动这一目标所需的技能 随着我成长为一名独立的精神病学家-神经学家，我进行了研究。

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.