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

项目概要 药物滥用造成重大健康威胁，造成数十亿美元的损失和数千人的生命 每年一次，目前对于阿片类药物和可卡因来说尤其严重。对于易感人群，药物 滥用行为劫持了控制动机和决策的大脑回路，导致人们不断寻求 药物，尽管使用它们会产生有害后果。即使人们决定停止越来越多的 适应不良的药物使用，在大多数情况下最终会复发。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工作的 大脑，为此我们需要与翻译相关的动物模型。在这里，我采用这样的模型，结合 使用细胞类型和途径特异性化学遗传学 (DREADD) 操作方法来了解如何 他们处理有关可卡因和阿片类芬太尼类似物的决策，以及自然奖励。我 重点关注腹侧苍白球（VP）回路在成瘾相关行为中的作用。迄今为止，我已经证明了 VP 神经元被可卡因复吸诱导信号激活，并且化学遗传学 VP 抑制 减少自愿戒断后的类似复发的行为，尤其是在最强迫性的可卡因- 寻找个体（目标 1.1）我还表明，VP GABA 表达的选择性化学遗传学抑制 神经元减弱了追求美味食物时的冒险决策行为，并减少了工具性的 做出反应既是为了追求有价值的食物，也是为了避免受到震惊，这表明了一个基本的作用 对于这些神经元来说，无论价态如何，其动机都不同（目标 1.2）。这个奖项的F99阶段将转移我的注意力 持续的健康危机：阿片类药物流行。我首先确认我对 VP GABA 神经元的初步发现 参与阿片类药物复发的寻求，使用一种新的惩罚诱导的戒断复发程序，该程序 模拟人类自愿戒烟后的复发（目标 2.1）。目标 2.2 涉及更广泛的电路，其中 VP 旨在调节与成瘾相关的动机。具体来说，我们使用特定于途径的 DREADD 抑制方法来测试 VP GABA 对 VTA 的投射是否与阿片类药物成瘾有关。 拟议的培训将有助于我过渡到专注于体内的竞争性博士后职位 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 与致力于解决成瘾问题的教师一起创造刺激、协作的研究环境 多个级别，拥有大量技术资源、指导培训机会和专业人士 开发研讨会。总而言之，F99/K00 对于让我走上终身教职和终身职位的道路来说是无价的。 超越成瘾行为神经科学家。

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.