Ventral pallidum activity links motivationally attractive cues together for sign-tracked behavior

腹侧苍白球活动将动机上有吸引力的线索联系在一起，以形成信号跟踪行为

• 批准号: 9907288
• 负责人: Elizabeth Smedley
• 金额: $ 3.43万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-11 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907288
• 关键词: Animal Model; Animals; Area; Behavior; Behavioral; Bilateral; Brain; Brain Stem; Choice Behavior; Code; Conditioned Reflex; Consumption; Cues; Desire for food; Development; Disease; Distal; Drug Addiction; Eating; Electrodes; Electrophysiology (science); Environment; Extinction (Psychology); Globus Pallidus; Human; Implant; Interruption; Joints; Learning; Link; Mediating; Modeling; Motivation; Nature; Neurobiology; Neurons; Outcome; Paper; Performance; Pharmaceutical Preparations; Phase; Play; Population; Procedures; Publishing; Relapse; Rewards; Role; Series; Signal Transduction; Site; Smell Perception; Stimulus; Structure; Substance Addiction; Substance abuse problem; Testing; Therapeutic; Time; Training; Update; Work; addiction; classical conditioning; clinically relevant; conditioning; cue reactivity; experimental study; follow-up; hedonic; in vivo; insight; novel therapeutics; optogenetics; performance tests; relating to nervous system; response

Project Summary The ventral pallidum (VP) is a diversely interconnected structure with major inputs from cortical, limbic, and brainstem areas. Studies show the VP is necessary for reward learning and performance, motivation, and hedonic functioning. Despite its clinical relevance serving as arguably one of the most crucial sites for reward and motivation in the brain, how neurons in the VP encode motivational signals remains far from resolved. A dysregulation of reward and motivation, particularly in the domain of heightened reward cue-reactivity, is thought to serve as a major factor in substance abuse disorders. One model for examining brain mechanisms in animals is motivational attraction to cues that are paired with reward seen in autoshaping, often called sign- tracking. Sign-tracking animals will heavily interact with a stimulus which predicts a reward outcome, even though their response does not affect the delivery of the reward. Sign-tracking animals share similar behavioral and neurobiological responses to those evoked by addictive drugs. Critically, the vast majority of autoshaping paradigms use only a single cue to predict reward, while it is more common in the real world that a series of cues predict a rewarding outcome (i.e., a grinder and rolling papers precede the creation of a joint). My previous work used a Sequential Lever Pavlovian Conditioning Paradigm (SLPCP), where lever cues were inserted in temporal sequence prior to reward delivery (distal lever à proximal lever à reward delivery). I was able to show that cues that occur temporally distal to reward will gain greater sign-tracking interactions than temporally proximal cues over sessions (i.e., a distal lever bias), suggesting that distal cues carry more motivational draw. Further, I found evidence that these cues form a representational link with one another; removing the value of one cue (via extinction procedures) immediately updates the value of the associated cue as seen in cue-mediated reductions in sign-tracking. In order to discern how VP comes to represent cues in the environment and their relationships with other cues in sequence, in vivo electrophysiological recordings of VP during SLPCP behavior will be employed. The proposal will test the hypothesis that VP neuronal activity emerges to encode the motivational value of the serial cues, with a representational bias towards the distal cue, and that activity of VP neurons can be shared across both cues in a manner that reflects a shared value (Aim 1). To show that VP plays a causal role in the development of this cue relationship, I will optogenetically inhibit VP during the presentation of the distal cue only during acquisition to specifically reduce the distal lever bias behavioral effect. Later, distal lever extinction will show that animals who received VP inhibition during the distal cue early on will not effectively update the value of the proximal cue in test sessions (i.e., the shared value representation was blocked from occurring; Aim 2). Together, findings from this project will show the critical role that VP plays in cue-driven behavior and how acquisition of those conditioned responses can be specifically manipulated and impact later behavior. Moreover, if hypotheses are met and the motivational value of the full cue sequence occurs as a unit that can be reduced by disruption of one cue-reward relationship, the project will raise new therapeutic possibilities to treat addiction and relapse.

项目摘要 腹侧苍白球（VP）是一个由皮质、边缘和海马神经元传入的神经元相互连接的结构。 脑干区研究表明，副总裁是必要的奖励学习和表现，动机， 享乐功能尽管它的临床相关性可以说是最重要的奖励网站之一， 然而，VP中的神经元如何编码动机信号仍然远未解决。 奖励和动机的失调，特别是在提高奖励线索反应性的领域， 被认为是药物滥用障碍的主要因素。一个研究大脑机制的模型 在动物中，是对线索的动机吸引力，这些线索与在自动成形中看到的奖励配对，通常被称为符号， 跟踪.跟踪信号的动物会与预测奖励结果的刺激物进行大量互动， 虽然他们的反应并不影响奖励的发放。追踪信号的动物有着相似的行为 和神经生物学的反应。重要的是，绝大多数自动整形 范式只使用一个单一的线索来预测奖励，而在真实的世界中， 线索预测奖励结果（即，研磨机和卷纸先于接合部的形成）。我 以前的工作使用了一个顺序杠杆巴甫洛夫条件反射范式（SLPCP），其中杠杆线索是 在奖励传递之前按时间顺序插入（远端杠杆→近端杠杆→奖励传递）。我 能够表明，在时间上远离奖励的线索将获得比 会话上的时间上接近的线索（即，远端杠杆偏置），表明远端线索携带更多的 动机性平局此外，我发现证据表明，这些线索形成了一个代表性的联系，彼此; 移除一个提示的值（通过消除过程）立即更新相关提示的值 如在信号追踪中的线索介导的减少中所见。 为了辨别VP如何来代表环境中的线索以及它们与其他人的关系， 线索的顺序，在SLPCP行为期间VP的体内电生理记录将被采用。的 该提案将测试VP神经元活动出现编码的动机价值的假设， 串行线索，具有对远端线索的代表性偏见，VP神经元的活动可以共享 以反映共同价值的方式跨越两个线索（目标1）。为了说明VP在这个过程中起着因果作用， 为了发展这种线索关系，我将在远端线索的呈现期间光遗传学地抑制VP 仅在采集期间，以专门减少远端杠杆偏置行为效应。后来，远端杠杆熄灭 将表明，在远端线索早期接受VP抑制的动物将不能有效地更新 测试会话中的邻近提示的值（即，共享值表示被阻止发生; 目标2）。总之，本项目的研究结果将显示VP在线索驱动行为中发挥的关键作用， 这些条件反射的获得是如何被具体操纵并影响后来的行为的。 此外，如果假设得到满足，并且完整提示序列的激励价值作为一个单元出现， 通过破坏一个线索-奖励关系，该项目将提出新的治疗可能性， 治疗成瘾和复发。