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，包括成瘾的升级。 药物使用和即使在长期禁欲后复发的倾向。具有高激励价值的线索 可以驱动与个人目标和期望价值脱节的寻求奖励的行为， 结果（奖励或惩罚）。这可能导致持续或强迫性的药物使用， 不良后果。在以神经调节为基础的成瘾治疗中， 关于参与线索驱动的奖励寻求行为的电路的知识，以及这些电路是如何 与那些涉及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。这项建议的重点是腹侧苍白球（VP）的作用， 基底前脑对吸毒复发和积极情绪都至关重要。我们的目标是找出 VP神经群体编码的线索的激励价值，以及神经回路机制， 线索驱动动机行为。我们的中心假设是，代表激励价值的神经元 提示与那些代表未来结果的预期值的提示不同，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，在这个群体中的活动是至关重要的 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价值和结果的预期价值的编码， VP中的单个神经元。我们的假设是VP中独立的神经元编码激励值和期望值， 值我们将使用在体单单位电生理学来测量个别VP神经元的活动模式 并确定这些神经元的活动是否预测了线索- 引发的寻求奖励行为和/或预测结果的当前预期值。在目标2中， 识别编码线索激励值的VP输出路径。我们的假设是VP神经元 编码激励值是GABA能的并投射到VTA。我们将使用光纤测光来测量 在奖赏提示过程中投射到腹侧被盖区或丘脑的VP GABA神经元的钙信号 并确定这些群体中的活动是否预测线索引发的奖励寻求行为和/或 期望值。在目标3中，我们将测试这些VP输出通路中活动的功能作用， 对线索的反应这项研究的成功完成将表征激励的大脑机制 价值表征，并定义下游回路目标，以激励行为， VP激励价值信号。我们对这些电路的理解的进步将有助于 针对强迫性药物使用的神经机制的基于大脑的治疗的改进。

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.