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

项目摘要 腹侧苍白球(VP)是一种不同的相互联系的结构，主要输入来自皮质、边缘和 脑干区。研究表明，副总裁对于奖励学习和表现、激励和 享乐功能。尽管它与临床相关，但可以说是最关键的奖励地点之一 而大脑中的动机，VP中的神经元如何编码动机信号，仍然远未解决。 奖赏和动机的失调，特别是在奖赏线索反应性增强的领域，是 被认为是药物滥用障碍的主要因素。一种检测大脑机制的模型 在动物中，是对线索的动机吸引，这些线索与自动成形中看到的奖励相匹配，通常被称为符号- 追踪。手势跟踪动物将与预测奖励结果的刺激严重互动，甚至 虽然他们的反应并不影响赏金的发放。追踪手势的动物有相似的行为 以及对那些由成瘾药物引起的神经生物学反应。关键的是，绝大多数的自动整形 范式只使用一个线索来预测奖励，而在现实世界中更常见的是一系列 暗示预示着一个有益的结果(即，在创建关节之前，先使用研磨机和卷纸)。我的 以前的工作使用了顺序杠杆巴甫洛夫条件反射范式(SLPCP)，其中杠杆线索 在提供奖励之前按时间顺序插入(远端杠杆和近端杠杆)。我曾经是 能够显示出现在时间上远离奖励的提示将获得更大的手势跟踪交互作用 短时近端线索超过会话(即，远端杠杆偏向)，表明远端线索承载更多 励志抽签。此外，我发现有证据表明，这些线索彼此之间形成了一种代表性联系； 删除一个球杆的值(通过消光程序)会立即更新相关球杆的值 从线索调节的手势跟踪减少中可以看到这一点。 为了辨别VP如何呈现环境中的线索以及它们与他人的关系 按照提示顺序，将采用SLPCP行为过程中VP的在体电生理记录。这个 该提案将检验VP神经元活动出现以编码 序列线索，对远端线索有代表性偏向，VP神经元的活动可以共享 以反映共同价值的方式跨越这两个线索(目标1)。以表明VP在这一事件中起因果作用 这种线索关系的发展，我会在远端线索的呈现过程中对VP产生光遗传抑制 只有在习得过程中才能具体降低远端杠杆偏向的行为效应。后来，远端节肢灭绝 将表明，在远端线索早期接受VP抑制的动物将不会有效地更新 测试会话中近端提示的值(即，共享值表示被阻止出现； 目标2)。总而言之，这个项目的发现将表明VP在线索驱动的行为中扮演的关键角色 这些条件性反应的获得如何被特定地操纵并影响后来的行为。 此外，如果满足假设，并且完整线索序列的激励值作为一个单位出现，则可以 由于一个提示-奖励关系的中断而减少，该项目将提高新的治疗可能性 治疗上瘾和复发。

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.