Ventral Pallidum Circuits in Motivation, Risky Decision Making, and Opioid Addiction

项目摘要 物质使用障碍是一个重大的健康威胁，造成数十亿美元和数千人的生命损失 每年，这对阿片类药物和可卡因来说尤其严重。在易感人群中，药物 滥用劫持了控制动机和决策的大脑回路，导致继续寻求 尽管使用毒品会带来有害的后果，但仍有必要采取行动。即使当人们决定停止他们日益增长的 不适应药物使用，在大多数情况下，他们最终会复发。为了帮助那些试图戒毒的人 保持节制，我们必须了解动机和决策的潜在神经回路是如何在 大脑，为此，我们需要翻译相关的动物模型。在这里，我采用了这样的模型，加上 使用细胞类型和途径特异性化学发生(DREADD)操作方法来了解 他们处理关于可卡因和阿片类芬太尼类似物的决策，以及自然奖励。我 关注腹侧苍白球(VP)回路在成瘾相关行为中的作用。到目前为止，我已经证明 VP神经元是由可卡因复发诱导线索激活的Fos，而化学合成VP抑制 减少自愿戒除后复发的行为，特别是在最强迫性的可卡因- 寻找个体(目标1.1)I还表明选择性化学发生抑制VP-GABA的表达 神经元减少了追求美味食物的危险决策行为，并减少了工具性 在追求有价值的食物和避免震惊的同时做出反应，这表明了一个基本的角色 对于这些神经元的动机，而不考虑价态(目标1.2)。这个奖项的F99阶段将转移我的注意力 一个持续的健康危机：阿片类药物的流行。我首先确认我对VP-GABA神经元的初步发现 参与阿片类药物寻求的复发，使用一种新的惩罚诱导戒断复发程序， 建立自愿禁欲后复发的模型(目标2.1)。AIM 2.2介绍了VP在更广泛的电路中 是用来调节与成瘾有关的动机的。具体地说，我们使用路径特定的DREADD 采用抑制法检测VPGABA向VTA的投射是否与阿片成瘾有关。 拟议的培训将有助于我过渡到一个具有竞争力的博士后职位，专注于体内研究 电路监测，这将与我在成瘾行为模型和化学发生方面的专业知识相吻合 电路操作。通过建立欧文成瘾神经科学中心，UCI提供了 激励、协作的研究环境，教师致力于解决成瘾问题 多个级别，拥有大量技术资源、导师培训机会和专业人员 发展研讨会。总而言之，F99/K00对于让我走上终身教职的轨道将是无价的 Beyond是一名上瘾行为神经学家。

Project Summary Substance use disorder poses a major health threat that costs billions of dollars and thousands of lives annually, and which is especially acute right now for opioid drugs and cocaine. In susceptible individuals, drugs of abuse hijack brain circuits that govern motivation and decision making, leading to continued seeking of drugs despite harmful consequences of using them. Even when people decide to cease their increasingly maladaptive drug use, in most cases they end up relapsing. In order to help those trying to quit using drugs to stay abstinent, we must understand how underlying neural circuits of motivation and decision making work in the brain, and for this we need translationally-relevant animal models. Here, I employ such models, coupled with cell-type and pathway-specific chemogenetic (DREADD) manipulation approaches to understand how they process decision making about cocaine and an opioid fentanyl analogue, as well as for natural rewards. I focus on the role of ventral pallidum (VP) circuits in addiction-relevant behaviors. To date, I have shown that VP neurons are Fos activated by cocaine-relapse-inducing cues, and that chemogenetic VP inhibition diminishes relapse-like behavior following voluntary abstinence, especially in the most compulsively cocaine- seeking individuals (Aim 1.1) I also showed that selective chemogenetic inhibition of VP GABA-expressing neurons attenuates risky decision making behavior in pursuit of palatable food, and decreases instrumental responding both in pursuit of valuable foods, and in avoidance of being shocked, indicating a fundamental role for these neurons in motivation regardless of valence (Aim 1.2). The F99 phase of this award will shift my focus to an ongoing health crisis: the opioid epidemic. I first confirm my preliminary finding of VP GABA neuron involvement in relapse to opioid seeking, using a new punishment-induced abstinence relapse procedure that models human relapse after voluntary abstinence (Aim 2.1). Aim 2.2 addresses the wider circuits in which VP is embedded to regulate addiction-related motivation. Specifically, we use a pathway-specific DREADD inhibition approach to test whether VP GABA projections to VTA in particular are involved in opioid addiction. The proposed training will facilitate my transition to a competitive postdoctoral position focused on in vivo circuit monitoring, which will dovetail with my expertise in addiction behavioral models, and chemogenetic circuit manipulations. Through establishment of the Irvine Center for Addiction Neuroscience, UCI offers a stimulating, collaborative research environment with faculty dedicated to solving the problem of addiction at the multiple levels with a host of technical resources, mentorship training opportunities, and professional development workshops. In sum, the F99/K00 will be invaluable for keeping me on a track to tenure and beyond as an addiction behavioral neuroscientist.