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）高度合并，导致更糟 症状的严重程度和治疗结果比单独的疾病。有Oud的人似乎是 特别容易受到PTSD的影响。孤立研究每种疾病都无法捕获 PTSD和OUD之间的相互关系。虽然先前的创伤往往发生在发展之前 物质使用障碍，对这种关系的因果机制知之甚少。 PTSD和OUD 可以将其概念化为学习障碍，其中阿片类药物或恐惧相关的提示强烈控制 行为。为了促进我们对PTSD和OUD合并症的理解，这一建议的目标 研究是为了阐明压力引起的神经适应，这可能会促进阿片类药物的脆弱性 学习和奖励。 球迷实验室已经开发了一个压力源模型，该模型概括了一些症状。 PTSD。在这种压力源模型中，严重的压力使未来的恐惧学习敏感。我证明了严重的压力 此外，增强了未来的阿片类替代性学习。这种压力源模型和阿片类药物的学习都是 取决于基底外侧杏仁核（BLA）活性。压力增强了兴奋性和神经可塑性 BLA，导致令人着迷的可能性，严重的压力从根本上改变了学习过程 Bla，使个人更容易受到阿片类药物奖励学习的影响。使用新型活动依赖性标签 大鼠模型中的技术，该提案的第一个目的将检查神经元是否存在显着重叠 通过严重的应力和吗啡膜的配对激活。这样的发现将提供证据表明神经元 对严重压力的反应直接参与未来的阿片类药物奖励提示学习。该提议的第二个目标 将检查压力响应性神经元是否需要增强阿片类药物学习。这项工作将 促进涉及复杂行为方法的结合的跨学科培训经验 与体内化学发生，体内活性依赖性标记和离体分析技术搭配 最终扩大了我们对创伤压力如何导致OUD发展的理解。这些 实验将在UCLA进行，这是一个优先级生产率的出色培训环境， 指导和协作，确保项目的成功。