Neural basis of incentive and expected value representations

项目摘要 药物相关线索的激励价值驱动成瘾的几个方面，包括成瘾升级 吸毒和即使在长期戒毒后也有复发的倾向。具有较高激励价值的线索 会驱使追求奖励的行为与个人的目标和期望价值脱节 结果(即奖励或惩罚)。这可能导致持之以恒或强制使用药物，尽管 不利的后果。基于神经调节的成瘾治疗进展的一个关键障碍是缺乏 关于参与线索驱动的奖赏行为的回路的知识，以及这些回路如何 与那些参与目标导向行为的人不同，目标导向行为依赖于准确的心理表征 预期结果及其价值。这项建议侧重于腹侧苍白球(VP)的作用，这是一个 对吸毒复发和积极情绪起关键作用的基底前脑。我们的目标是找出 对线索的激励值进行编码的VP神经种群，以及通过其 暗示会驱动有动机的行为。我们的中心假设是，代表刺激价值的神经元 线索不同于那些代表未来结果的期望值的线索，这些神经元可以 根据输出路径进行定义。我们预测GABA能VP神经元的活动投射到 腹侧被盖区(VTA)编码线索驱动的奖赏寻求，这一群体的活动是至关重要的 用于线索驱动的动机行为。我们将通过追求以下目标来检验我们的假设。 在目标1中，我们将研究线索的激励值和结果的期望值的编码 VP内的单个神经元。我们的假设是，VP中的独立神经元编码激励价值和预期 价值。我们将使用活体单个单位电生理学来测量单个VP神经元的活动模式 在呈现与奖励相关的线索时，并确定这些神经元的活动是否预测线索- 引发了寻求奖励的行为和/或预测结果的当前期望值。在《目标2》中我们将 识别编码线索激励价值的VP输出通路(S)。我们的假设是VP神经元 编码激励价值的是GABA和投射到VTA。我们将使用光纤光度法来测量 VP-GABA神经元在呈现奖赏线索时投射到VTA或丘脑的钙信号 并确定这些人群中的活动是否预测了线索引发的奖励行为和/或 期望值。在目标3中，我们将测试活动在这些VP输出通路中的功能作用 对暗示的反应。这项研究的成功完成将表征激励的大脑机制 值表示，并定义用于激励行为的激励行为的下游电路目标 副总裁激励价值信号。我们对这些电路的了解的进步将有助于 改进以大脑为基础的疗法，针对强迫药物使用的神经机制。

Project Summary The incentive value of drug-associated cues drives several facets of addiction, including escalation of drug use and the propensity to relapse even after long periods of abstinence. Cues with high incentive value can drive reward-seeking behaviors that are disconnected from an individual’s goals and the value of expected outcomes (i.e. rewards or punishments). This may lead to perseverative or compulsive drug use despite adverse consequences. A critical barrier to progress in neuromodulation-based treatments for addiction is lack of knowledge regarding the circuits engaged in cue-driven reward-seeking behavior, and how these circuits are distinct from those involved in goal-directed behavior, which relies on accurate mental representations of expected outcomes and their value. This proposal focuses on the role of the ventral pallidum (VP), a region of the basal forebrain that is critical for both relapse to drug use and positive affect. Our objective is to identify the VP neural populations that encode the incentive value of cues, and the neural circuit mechanisms by which cues drive motivated behavior. Our central hypothesis is that neurons that represent the incentive value of cues are distinct from those that represent the expected value of future outcomes, and that these neurons can be defined based on output pathway. We predict that the activity of GABAergic VP neurons projecting to the ventral tegmental area (VTA) encodes cue-driven reward-seeking and that activity in this population is critical for cue-driven motivated behavior. We will test our hypothesis by pursuing the following aims. In Aim 1 we will examine encoding of the incentive value of cues and expected value of outcomes by individual neurons in VP. Our hypothesis is that separate neurons in VP encode incentive value and expected value. We will use in vivo single unit electrophysiology to measure activity patterns in individual VP neurons during presentations of reward-related cues and determine whether activity in these neurons predicts cue- elicited reward-seeking behavior and/or the current expected value of a predicted outcome. In Aim 2 we will identify the VP output pathway(s) that encode the incentive value of cues. Our hypothesis is that VP neurons that encode incentive value are GABAergic and project to the VTA. We will use fiber photometry to measure calcium signals in VP GABA neurons projecting to the VTA or thalamus during presentations of reward cues and determine whether activity in these populations predicts cue-elicited reward-seeking behavior and/or expected value. In Aim 3 we will test the functional role of activity in these VP output pathways in behavioral responses to cues. Successful completion of this research will characterize the brain mechanisms of incentive value representations and define the downstream circuit targets for the invigoration of motivated behavior by VP incentive value signals. Advancements in our understanding of these circuits will contribute to the refinement of brain-based therapies that target the neural mechanisms underlying compulsive drug use.