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

基底外侧杏仁核中的神经元群及其在伏隔核中的投射目标对阿片类药物驱动的接近和回避行为的控制

• 批准号: 10449911
• 负责人: Hermina Nedelescu
• 金额: $ 17.33万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449911
• 关键词: Address; Affect; Amygdaloid structure; Anatomy; Area; Aversive Stimulus; Axon; Behavior; Behavior Control; Behavioral; Behavioral Model; Brain; Brain Diseases; Brain region; Chronic; Data; Desire for food; Development; Development Plans; Drug Controls; Drug Modelings; Environment; Event; Future; Genes; Glutamates; Goals; Investigation; Knowledge; Laboratory Research; Lead; Learning; Link; Mediating; Mentors; Mentorship; Molecular; Molecular Target; Morphine; Naloxone; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Opioid; Opioid Antagonist; Opioid agonist; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Presynaptic Terminals; Process; Recurrent disease; Relapse; Research; Research Design; Rewards; Role; Sensory Process; Signal Transduction; Site; Source; Stimulus; System; Testing; Training; approach avoidance behavior; approach behavior; avoidance behavior; base; career; career development; conditioned place preference; drug of abuse; drug seeking behavior; experience; hippocampal pyramidal neuron; insight; motivated behavior; neural circuit; neurochemistry; novel; opioid use disorder; optogenetics; programs; recruit; research and development; response; skills; success; tool; transmission process; treatment strategy

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.

项目总结/摘要 阿片类药物使用障碍（OUD）是一种慢性、复发性脑部疾病，以强迫性药物滥用为特征 寻求和使用，参与特定的神经回路。其中一个主要的投影系统涉及到调节 由滥用药物（包括阿片类药物）引起的行为是基底外侧杏仁核（BLA）通路 （NAc）.然而，BLA CAMNAc投射不仅介导接近行为，如 药物寻求，但也回避反应。这就引出了一个问题： 单个兴奋性投射系统介导完全相反的行为。我们的初步数据显示， 吗啡（一种奖赏性阿片激动剂）和纳洛酮（一种厌恶性阿片拮抗剂）招募两个不同的群体 在同一个（BLA）大脑区域内的神经元-神经元集合或记忆痕迹。此外，选择性激活 吗啡和纳洛酮反应性BLA轴突终末在NAc诱导的相反条件性位置偏爱中的作用 (CPP)分别为：这些初步数据确立了两种离散的药物反应性 NAc投射的BLA合奏每个差异和选择性敏感的激活奖励（吗啡） vs.引起接近与回避行为的获得的厌恶（纳洛酮）事件。基于这些 结果，我们推测CPP和CPA的表达也是由相似的不同的BLA β NAc介导的 选择性地对吗啡与纳洛酮环境背景敏感的集合。为了支持这一假设， 另外的初步研究结果证实，吗啡CPP和纳洛酮CPA的表达是 伴随着BLA和NAc中的神经元激活。本提案的目的是确认 吗啡与纳洛酮情境反应性BLA NAc集合对CPP/CPA表达的影响，以及 建立支配这两种不同的BLA-NAc集合的全脑激活源， 相反的行为。因此，K 01提案将检验中心假设，即环境背景 与吗啡（Aim 1）和纳洛酮（Aim 2）相关联，募集离散的NAC投射BLA集合， 由来自大脑区域的兴奋性输入（Aim 3）激活，这些大脑区域处理代表相应 背景，从而使离散的BLA ARANAc集合选择性地调节接近与回避 行为在斯克里普斯研究所的弗里德伯特韦斯博士的主要指导下， 一个全面的研究和职业发展计划，以获得必要的实验和 专业技能在协作神经科学环境。经验丰富的导师和职业团队 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： 在研究设计、执行和解释药物寻求行为模型方面的教学式学习， 刺激反应激活的神经元。最后，专业发展计划将使候选人能够 领导一个实验室研究项目，调查不同的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，包括行为相关的神经回路。