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

项目总结 与奖励相关的感觉线索让我们能够预测未来的结果，并相应地调整行为。 然而，奖励预测线索获得了激励和强化的特性，使它们能够捕捉到 注意力和强烈的偏向于追求回报的行为。例如，预测药物的线索可能会引发 强烈的欲望和持续的强迫性毒品寻觅。这些线索的影响会导致慢性高血压的风险。 成瘾复发，这对患者的长期预后是一个重大挑战。腹侧苍白球(VP)是一种 前脑核对线索诱导行为表达的关键作用，包括线索诱导的临床前模型 旧病复发。最近的研究表明，腹侧被盖区(VTA)的VP投射对于 线索诱导的药物寻找的恢复，但潜在的神经生物学和心理机制 这条通路(VP、→、Vta)是通过什么途径来调节线索诱发的奖赏寻求的，目前尚不清楚。以前的工作没有 试图分离这一途径对激活和加强线索特性的贡献。 澄清这些机制对于改进基于电路的动机行为模型和生成 包括成瘾在内的动机障碍的翻译相关模型。因此，该委员会的总体目标是 建议的工作是阐明奖励预测线索动态调节的机制 VP、→、VTA的活动与奖赏行为的中介作用。 该方案的总体目标是：1)表征线索诱发过程中VP-VTA投射的值编码 2)表征了VP→VTA活动的调节对线索诱导的奖赏的影响。 寻找。由于GABA能VP神经元通常促进欲望奖赏寻求，我的目标是GABA能 投射到VTA的VP神经元(VPGABA、→、VTA)。从我实验室的初步数据来看 增强和并行工作中的VP→Vta识别编码奖励预测误差的VP神经元 与强化学习模型典型相关的信号，我假设VPGBA→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 用光度法记录(目标1)和光遗传学操纵(目标2)线索诱导的这一途径 行为。在这些目标下提出的实验将促进我们对神经机制的理解。 通过这些线索来激励和强化自然主义的奖赏追求。这些结果将解决 以前的文献，并作为未来调查副总裁和VTA在收购、升级、 以及强迫性行为的复发。此外，我将在设计和执行方面获得实质性的培训 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)自由行为动物的神经元亚群，并先进的定量 将神经活动与行为和决策变量联系起来的技巧。总体而言，执行的活动 这一奖项将为我作为一名独立研究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.