Control of opioid-motivated approach and avoidance behavior by neuronal ensembles in the basolateral amygdala and their projection targets in the nucleus accumbens

项目概要/摘要 阿片类药物使用障碍 (OUD) 是一种慢性、复发性脑部疾病，其特征是强迫性药物 寻找和使用，参与特定的神经回路。涉及监管的主要投影系统之一 滥用药物（包括阿片类药物）引发的行为是基底外侧杏仁核 (BLA) 通往核的途径 伏隔核（NAc）。然而，BLANAc 投影不仅调节接近行为，正如 寻求药物，但也有回避反应。这就引入了关于机制的问题 单一的兴奋性投射系统介导截然相反的行为。我们的初步数据显示 吗啡（一种有益的阿片类激动剂）和纳洛酮（一种令人厌恶的阿片类拮抗剂）招募两个不同的群体 同一 (BLA) 大脑区域内的神经元（神经元集合或印迹）。此外，选择性激活 吗啡与纳洛酮反应性 BLA 轴突末端在 NAc 中诱导的相反条件位置偏好 分别为（CPP）和厌恶（CPA）。这些初步数据确定了两种离散药物反应的作用 NAc 投射的 BLA 整体对奖励（吗啡）的激活有不同的选择性敏感 与引发接近行为和回避行为的厌恶（纳洛酮）事件。基于这些 结果，我们假设 CPP 和 CPA 的表达也由类似的不同 BLANAc 介导 整体对吗啡和纳洛酮环境背景选择性敏感。为了支持这一假设， 其他初步结果证实吗啡 CPP 和纳洛酮 CPA 的表达 伴随着 BLA 和 NAc 中的神经元激活。该提案的目标是确认该功能 吗啡与纳洛酮环境反应性 BLANAc 整体的 CPP/CPA 表达，以及 建立全脑激活源来支配这两个不同的 BLANAc 系综 反对行为。因此，本 K01 提案将检验以下中心假设：环境背景 与吗啡（目标 1）和纳洛酮（目标 2）相关联招募离散的 NAc 投影 BLA 系综，这些系综是 由处理代表各自信息的大脑区域的兴奋性输入（目标 3）激活 环境，从而利用离散的 BLANAc 整体来选择性地调节接近与回避 行为。该培训计划在斯克里普斯研究中心的 Friedbert Weiss 博士的主要指导下提供 一个全面的研究和职业发展计划，以获得必要的实验和 协作神经科学环境中的专业技能。经验丰富的导师和职业团队 顾问将为候选人的短期和长期成功提供至关重要的培训，包括： 研究设计、执行和解释药物寻求行为模型的教学学习 对刺激反应激活的神经元。最后，职业发展计划将使候选人能够 领导一项实验室研究计划，通过不同的方法研究药物寻求行为的神经生物学控制 分布在多个大脑区域的神经元集合，包含行为相关的神经回路。

Project Summary / Abstract Opioid Use Disorder (OUD) is a chronic, relapsing brain disease characterized by compulsive drug seeking and use, engaging specific neurocircuits. One of the major projection systems implicated in regulating behavior motivated by drugs of abuse including opioids is the basolateral amygdala (BLA) pathway to nucleus accumbens (NAc). However, the BLANAc projection mediates not only approach behavior, as required for drug seeking, but also avoidance responses. This introduces the question as to the mechanisms by which a single excitatory projection system mediates diametrically opposite behaviors. Our preliminary data revealed that morphine (a rewarding opioid agonist) and naloxone (an aversive opioid antagonist) recruit two distinct groups of neurons – neuronal ensembles or engrams – within the same (BLA) brain area. Moreover, selective activation of morphine vs. naloxone reactive BLA axon terminals in the NAc induced opposing conditioned place preference (CPP) and aversion (CPA) respectively. These preliminary data establish a role for two discrete drug-reactive NAc-projecting BLA ensembles each differentially and selectively sensitive to activation by rewarding (morphine) vs. aversive (naloxone) events which elicit the acquisition of approach vs. avoidance behavior. Based on these results, we hypothesize that the expression of CPP and CPA are also mediated by similarly distinct BLANAc ensembles selectively sensitive to morphine vs. naloxone environmental context. In support of this hypothesis, additional preliminary findings confirmed that the expression of morphine CPP and naloxone CPA are accompanied by neuronal activation in both the BLA and NAc. The goal of this proposal is to confirm the function of the morphine vs. naloxone context-reactive BLANAc ensembles for the expression of CPP/CPA, and to establish the brain-wide source of activation innervating these two distinct BLANAc ensembles mediating opposing behaviors. This K01 proposal will, therefore, test the central hypothesis that an environmental context linked to morphine (Aim 1) vs. naloxone (Aim 2) recruits discrete NAc-projecting BLA ensembles, which are activated by excitatory input (Aim 3) from brain areas that process information representing the respective context, thereby engaging discrete BLANAc ensembles to selectively regulate approach vs. avoidance behavior. The training plan, under the primary mentorship of Dr. Friedbert Weiss at Scripps Research, provides a comprehensive research and career development plan for acquiring the necessary experimental and professional skills within a collaborative neuroscience environment. An experienced team of mentors and career advisors will provide training critical for the candidate’s short- and long-term success, including: experiential and didactic learning in study design, execution, and interpretation of behavioral models of drug seeking with a focus on stimuli-responsive activated neurons. Finally, the professional development plan will equip the candidate to lead a laboratory research program investigating the neurobiological control of drug seeking behavior by distinct neuronal ensembles distributed across multiple brain areas comprising behaviorally relevant neurocircuits.