Probing the contribution of stress-responsive neurons in the basolateral amygdala to stress enhanced opioid learning

探讨基底外侧杏仁核中应激反应神经元对应激增强阿片类药物学习的贡献

• 批准号: 10676321
• 负责人: Jamie Elizabeth Mondello
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2024-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676321
• 关键词: Abstinence; Affect; Amygdaloid structure; Association Learning; Automobile Driving; Behavior; Behavioral; Collaborations; Communication; Confocal Microscopy; Cues; Desire for food; Development; Disease; Ensure; Environment; FOS gene; Fright; Funding; Future; Genetic; Goals; Health; Hyperactivity; Immediate-Early Genes; Immunohistochemistry; Individual; Institution; Label; Laboratories; Learning; Learning Disorders; Measures; Mediating; Mentorship; Modeling; Morphine; Motivation; NPAS4 gene; Neuronal Plasticity; Neurons; Opiate Addiction; Opioid; Population; Post-Traumatic Stress Disorders; Predisposition; Procedures; Process; Productivity; Property; Rattus; Research; Research Personnel; Rewards; Rodent; Role; Severities; Stimulus; Stress; Substance Use Disorder; Symptoms; Technical Expertise; Techniques; Testing; Training; Trauma; Treatment outcome; Viral; Viral Vector; Work; Writing; career; comorbidity; conditioned fear; conditioned place preference; craving; design; experience; experimental study; genetic manipulation; in vivo; nerve supply; neural; neuroadaptation; neuromechanism; novel; opioid use; opioid use disorder; psychologic; skills; stressor; success; traumatic stress

Project Summary/Abstract Post-traumatic stress disorder (PTSD) and opioid use disorder (OUD) are highly comorbid, resulting in worse symptom severity and treatment outcomes than either disorder alone. Individuals with OUD appear to be particularly susceptible to PTSD. Studying each disorder in isolation fails to capture the complexity of the interrelationships between PTSD and OUD. While prior trauma tends to occur before the development of substance use disorders, little is known about the causal mechanism of this relationship. Both PTSD and OUD can be conceptualized as learning disorders, in which opioid- or fear-associated cues gain a strong control over behaviors. In order to advance our understanding of PTSD and OUD comorbidities, the goal of this proposed research is to shed light on the stress-induced neuroadaptations that may promote vulnerability for opioid learning and reward. The Fanselow laboratory has developed a stressor model that recapitulates some of the symptomology of PTSD. In this stressor model, severe stress sensitizes future fear learning. I demonstrated that severe stress additionally enhances future opioid-context learning. Both this stressor model and opioid-context learning are dependent on basolateral amygdala (BLA) activity. Stress enhances the excitability and neural plasticity in the BLA, leading to the intriguing possibility that severe stress fundamentally changes learning processes in the BLA, making individuals more susceptible to opioid reward learning. Using a novel activity-dependent labeling technique in a rat model, the first aim of this proposal will examine whether there is significant overlap in neurons activated by severe stress and morphine-context pairing. Such findings would provide evidence that neurons responsive to severe stress directly engage in future opioid-reward cue learning. The second aim in this proposal will examine if stress-responsive neurons are necessary for stress enhanced opioid learning. This work will promote an interdisciplinary training experience involving a combination of sophisticated behavioral approaches paired with in vivo chemogenetic, in vivo activity-dependent labeling, and ex vivo analysis techniques that will ultimately broaden our understanding of how traumatic stress can lead to development of OUD. These experiments will be conducted at UCLA, an excellent training environment that prioritizes productivity, mentorship, and collaboration, ensuring the success of the project.

项目摘要/摘要 创伤后应激障碍(PTSD)和阿片类药物使用障碍(OUD)高度并存，导致更糟糕的 症状严重程度和治疗结果比任何一种疾病本身都要好。患有自闭症的人似乎是 尤其容易患创伤后应激障碍。孤立地研究每一种疾病未能捕捉到 创伤后应激障碍与OUD之间的相互关系。而先前的创伤往往发生在 物质使用障碍，对这种关系的因果机制知之甚少。创伤后应激障碍和OUD 可以被概念化为学习障碍，在这种情况下，与阿片类药物或恐惧相关的线索获得了对 行为。为了增进我们对创伤后应激障碍和创伤后应激障碍并存的理解，我们建议 研究将阐明压力诱导的神经适应可能会增加阿片类药物的易感性 学习和奖励。 范斯洛实验室已经开发出一种压力源模型，它概括了一些症状 创伤后应激障碍。在这个压力源模型中，严重的压力会使未来的恐惧学习变得敏感。我证明了严重的压力 此外，还加强了未来的阿片类药物环境学习。这一应激源模型和阿片类情境学习都是 依赖于基底外侧杏仁核(BLA)的活动。应激增强大鼠的兴奋性和神经可塑性 BLA，导致了一种耐人寻味的可能性，即严重的压力从根本上改变了 血乳酸，使个人更容易受到阿片类奖励学习的影响。使用一种新的活性依赖标记 技术在大鼠模型中，这项建议的第一个目的是检查神经元是否有显著的重叠 被严重的压力和吗啡背景配对所激活。这些发现将提供证据，证明神经元 对严重压力的反应直接参与未来的阿片类奖赏线索学习。这项建议的第二个目的 将研究应激反应神经元是否对应激增强的阿片类药物学习是必要的。这项工作将 促进涉及复杂行为方法组合的跨学科培训体验 与体内化学发生、体内活性依赖的标记和体外分析技术相结合，将 最终拓宽了我们对创伤应激如何导致OUD发展的理解。这些 实验将在加州大学洛杉矶分校进行，这是一个非常好的培训环境，优先考虑生产率， 指导和协作，确保项目的成功。