Dissociating Invigoration and Reinforcement by GABAergic Ventral Pallidum Projections to the Ventral Tegmental Area During Cue-Elicited Reward-Seeking

项目摘要 与奖励相关的感官线索使我们能够预测未来的结果并相应地改变行为。 然而，奖励预测线索获得激励和强化属性，使他们能够捕捉 注意力和强有力的偏向行为有利于奖励追求。例如，药物预测线索可以触发 强烈的渴望和持续的强迫性药物寻求。这些线索的影响有助于慢性风险， 成瘾复发，对长期患者结局的重大挑战。腹侧苍白球（VP）是一个基底 前脑核对于线索诱发行为的表达至关重要，包括线索诱发行为的临床前模型。 复发最近的研究表明，VP投射到腹侧被盖区（VTA）是特别必要的， 线索诱导的药物寻求恢复，但潜在的神经生物学和心理机制 这条通路（VP→VTA）通过什么途径介导线索诱导的奖赏寻求尚不清楚。以前的工作没有 试图分离这条通路对刺激和强化线索的贡献。 澄清这些机制是必要的，以改善基于电路的动机行为模型，并产生 包括成瘾在内的动机障碍的认知相关模型。因此， 建议的工作是阐明奖励预测线索动态调节的机制 VP→VTA的活动并介导奖赏寻求行为。 该提议的总体目标是：1）表征在线索诱发期间VP-VTA投射的值编码， 奖励寻求和2）表征VP→VTA活动的调制对线索引起的奖励的影响- 寻找由于GABA能VP神经元通常促进食欲奖赏寻求，我的目标是靶向GABA能VP神经元， VP神经元投射至VTA（VPGABA→VTA）。根据我实验室的初步数据， VP→VTA在强化和并行工作中识别编码奖励预测错误（RPE）的VP神经元 信号规范与强化学习模型，我假设VPGABA→VTA编码RPE 并促进奖励和相关线索的强化价值。为了验证这一假设，我将使用体内纤维 在线索诱导期间，光度学记录（目的1）和光遗传学操纵（目的2）这一途径 行为根据这些目标提出的实验将促进我们对神经机制的理解 通过这些线索来激发和强化自然主义的奖励寻求。这些结果将解决 以前的文献，并作为未来工作的基础，调查VP和VTA在采购，升级， 和强迫行为的复发此外，我将获得大量的培训，在设计和执行 行为神经科学实验，具有多种操作方法的技术专长（光遗传学） 和记录（纤维光度法）神经元亚群在自由行为的动物，和先进的定量 将神经元活动与行为和决策变量联系起来的技能。总体而言， 这个奖项将为我作为一名独立研究人员的成功职业生涯做好准备。

PROJECT SUMMARY Sensory cues associated with reward allow us to predict future outcomes and modify behavior accordingly. However, reward-predictive cues acquire motivating and reinforcing properties which enable them to capture attention and powerfully bias behavior in favor of reward pursuit. Drug-predictive cues, for example, can trigger potent cravings and sustain compulsive drug seeking. The impact of such cues contributes to chronic risk of relapse in addiction, a significant challenge to long-term patient outcomes. The ventral pallidum (VP) is a basal forebrain nucleus critical for the expression of cue-elicited behavior, including preclinical models of cue-induced relapse. Recent work suggests VP projections to the ventral tegmental area (VTA) are specifically necessary for cue-induced reinstatement of drug seeking, yet the underlying neurobiological and psychological mechanisms by which this pathway (VP→VTA) mediates cue-elicited reward seeking are unknown. Previous work has not attempted to dissociate this pathway’s contributions to the invigorating and reinforcing properties of cues. Clarifying these mechanisms is necessary to improve circuit-based models of motivated behavior and generate translationally relevant models of motivational disorders including addiction. Thus, the broad objective of the proposed work is to elucidate mechanisms by which reward-predictive cues dynamically regulate activity of VP→VTA and mediate reward-seeking behavior. The overall goal of this proposal is to 1) characterize value encoding of VP-VTA projections during cue-elicited reward-seeking and 2) characterize the impact of modulations of VP→VTA activity on cue-elicited reward- seeking. Since GABAergic VP neurons generally promote appetitive reward seeking, I aim to target GABAergic VP neurons projecting to the VTA (VPGABA→VTA). Given preliminary data from my lab suggesting a role of VP→VTA in reinforcement and parallel work identifying VP neurons that encode reward-prediction error (RPE) signals canonically associated with reinforcement learning models, I hypothesize that VPGABA→VTA encode RPE and promote the reinforcing value of reward and associated cues. To test this hypothesis, I will use in-vivo fiber photometry to record from (Aim 1) and optogenetics to manipulate (Aim 2) this pathway during cue-elicited behavior. Experiments proposed under these Aims will advance our understanding of the neural mechanisms by which cues motivate and reinforce naturalistic reward-seeking. These results will resolve inconsistencies in prior literature and serve as a foundation for future work investigating VP and VTA roles in acquisition, escalation, and relapse of compulsive behavior. In addition, I will gain substantial training in the design and execution of behavioral neuroscience experiments, technical expertise with versatile methods to manipulate (optogenetics) and record (fiber photometry) neuronal subpopulations in freely behaving animals, and advanced quantitative skills for relating neuronal activity to behavior and decision-making variables. Collectively, activities performed under this award will prepare me for a successful career as an independent researcher.