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

项目摘要/摘要 阿片类药物使用障碍(OUD)是一种以强迫性药物为特征的慢性复发性脑部疾病 寻找和使用，激活特定的神经回路。与调控有关的主要投影系统之一 包括阿片类药物在内的滥用药物所激发的行为是杏仁基底外侧核(BLA)通往核团的通路 伏隔草(NAC)。然而，BLANAC预测不仅调解了进场行为，正如 寻求毒品，但也有回避反应。这就引出了一个问题，即一种 单一的兴奋投射系统调节截然相反的行为。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(一种厌恶的阿片类拮抗剂)招募了两个不同的群体 在相同的(BLA)大脑区域内的神经元-神经元集合或印记。此外，选择性激活 吗啡与纳洛酮反应的BLA轴突终末在NAc诱导的反向条件性位置偏爱中的比较 (CPP)和厌恶(CPA)。这些初步数据确定了两种不同药物反应的作用 NAC-投射BLA的每个集合对奖赏(吗啡)激活具有不同和选择性的敏感性 VS厌恶性(纳洛酮)事件，导致获得接近VS回避行为。基于这些 结果：我们假设Cpp和CpA的表达也是由相似的不同的BlaNAC介导的。 合奏对吗啡和纳洛酮的环境背景选择性敏感。为了支持这一假设， 进一步的初步研究证实，吗啡CPP和纳洛酮CPA的表达是 伴有BLA和NAC的神经元激活。这项提案的目标是确认功能 吗啡与纳洛酮上下文反应的BLANAC系综对CPP/CPA的表达，以及 建立全脑激活源，支配这两个不同的BlaNAC集合， 相反的行为。因此，这一K01提案将检验中心假设，即环境背景 与吗啡(AIM 1)VS纳洛酮(AIM 2)有关的是招募离散的NAC投射BLA合奏，这是 由来自大脑区域的兴奋性输入(目标3)激活，该区域处理代表各自的 背景，从而使离散的BLANAC合奏有选择地监管接近和避免 行为。在斯克里普斯研究公司Friedbert Weiss博士的主要指导下，该培训计划提供了 全面的研究和职业发展计划，以获得必要的实验和 在协作的神经科学环境中的专业技能。一支经验丰富的导师和职业生涯团队 顾问将提供对候选人的短期和长期成功至关重要的培训，包括：经验和 研究设计、实施和解释毒品寻觅行为模式的教学重点 刺激反应激活的神经元。最后，职业发展计划将使应聘者具备 领导一个实验室研究项目，调查药物寻觅行为的神经生物学控制 分布在多个大脑区域的神经元群组成了与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.