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

基于价值的决策，由每个人自己对可用报价的评估驱动，是不可或缺的 是我们生活的一部分，也是心理健康的关键决定因素。内化障碍（如抑郁、焦虑）， 通常具有适应不良的决策特征，其特征是将错误的低值分配给 奖励活动和物品。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，并可能提供翻译见解。外侧缰核（LHb）被认为是 作为大脑的"坏消息"中心，通过广播信号来降低奖励的价值， 与抑郁和类似焦虑的行为有关此外，已知LHb接收来自 中缝核，大脑中血清素的来源，一种神经调节剂，是大多数药物的目标， 内化障碍和许多其他精神病理学。中缝背核（DR），最大的神经元 核，是已知的参与价值相关的过程，虽然其输入LHb的作用尚不清楚。在 特别是，尽管其潜在的重要性，很少有人知道灵长类中缝-LHb电路如何介导的， 我们每天都在使用复杂的策略来选择活动和对象，这是一个决策过程， 需要集成许多奖励属性，例如金额、风险和延迟。我们假设 LHb在整合属性以计算报价和指导的价值方面起着核心作用 在线决策，使用从DR到折扣值的延迟相关信号。目标1研究了 多属性决策中的LHb。LHb信号被提出来反映跨 许多属性可以定义奖励，并最终传播到皮层和基底神经节， 在选择行动中起着重要作用。初步数据表明，LHb中的神经元整合了奖励 以与负主观价值一致的方式增加LHb发射， 在要约的陈述期间的电刺激以一致的方式使选择偏离该要约 降低报价价值。目的2研究DR多属性决策的作用。DR建议 来传递与奖励时间延迟相关的变量。如果在决策环境中这是真的，DR可以 将延迟和相关属性发送到LHb以指导决策。这个回路的中断会干扰 评估和选择多属性的报价，并通过抗抑郁药改善这种干扰， 有助于其治疗效果。随后的实验将检验以下假设： 这些目的将有助于阐明灵长类动物在延迟奖励中的作用 Raphe-LHb电路在多属性决策中的应用，为我将来的研究奠定了基础。 行为和神经系统，内在化和相关疾病的基础，毫无疑问， 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。 在我成长为一名独立的精神病学家和神经科学家的过程中，

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.