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

项目摘要 物质使用障碍造成了重大的健康威胁，造成数十亿美元和数千人的生命损失。 每年，这是特别严重的，现在阿片类药物和可卡因。在易感人群中，药物 滥用劫持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。即使人们决定停止他们日益增长的 使用适应不良的药物，在大多数情况下，他们最终复发。为了帮助那些试图戒烟的人， 保持禁欲，我们必须了解动机和决策的潜在神经回路是如何工作的， 大脑，为此，我们需要实验相关的动物模型。在这里，我采用这样的模型，耦合 细胞类型和途径特异性化学遗传学（DREADD）操作方法，以了解如何 他们处理关于可卡因和阿片类芬太尼类似物以及自然奖励的决策。我 重点是腹侧苍白球（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神经元是可卡因复吸诱导线索激活的Fos， 减少自愿戒断后的复发行为，特别是在最强迫性的可卡因- 寻找个体（目的1.1）我还表明，选择性化学发生抑制VP GABA表达， 神经元减弱了追求美味食物的风险决策行为， 在追求有价值的食物和避免被震惊的反应，表明一个基本的作用， 对于这些神经元的动机，无论效价如何（目标1.2）。这个奖项的F99阶段将转移我的重点 一场持续的健康危机：阿片类药物的流行。我首先证实了我的初步发现， 参与阿片类药物寻求复发，使用一种新的惩罚诱导的戒断复发程序， 自愿戒烟后的人类复发模型（目标2.1）。目标2.2涉及VP 是用来调节成瘾相关动机的具体来说，我们使用特定于路径的DREADD 抑制方法，以测试是否VP GABA投射到腹侧被盖区，特别是参与阿片类药物成瘾。 拟议的培训将有助于我过渡到一个有竞争力的博士后职位，重点是在体内 电路监测，这将与我在成瘾行为模型和化学遗传学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提供了一个 激励，协作研究环境与教师致力于解决成瘾问题，在 多层次的技术资源，指导培训机会和专业 发展研讨会。总之，F99/K 00将是无价的，让我走上了终身教职的轨道， 不仅仅是成瘾行为神经学家

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.