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: 10478904
• 负责人: Jamie Elizabeth Mondello
• 金额: $ 4.12万
• 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/10478904
• 关键词: Abstinence; Affect; Amygdaloid structure; Automobile Driving; Behavior; Behavioral; Collaborations; Confocal Microscopy; Cues; Desire for food; Development; Disease; Ensure; Environment; FOS gene; Fright; Funding; Future; Goals; Hyperactivity; Immediate-Early Genes; Immunohistochemistry; Individual; Institution; Label; Laboratories; Lead; Learning; Learning Disorders; Light; Measures; Mediating; Mental Health; Mentorship; Modeling; Morphine; Motivation; NPAS4 gene; Neuronal Plasticity; Neurons; Opiate Addiction; Opioid; Population; Post-Traumatic Stress Disorders; 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; classical conditioning; comorbidity; conditioned fear; conditioned place preference; craving; design; experience; experimental study; in vivo; nerve supply; neuroadaptation; neuromechanism; novel; opioid use; opioid use disorder; relating to nervous system; stressor; substance use; 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.

项目总结/摘要 创伤后应激障碍（PTSD）和阿片类药物使用障碍（OUD）高度共病，导致更严重的 症状严重程度和治疗结果。患有OUD的人似乎 特别容易患上创伤后应激障碍孤立地研究每一种疾病， PTSD和OUD之间的关系。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 可以被概念化为学习障碍，其中阿片类或恐惧相关的线索获得了对 行为。为了促进我们对PTSD和OUD合并症的理解，本研究的目标是 这项研究旨在揭示压力诱导的神经适应性，这种适应性可能会促进对阿片类药物的脆弱性。 学习和奖励。 Fanselow实验室开发了一个压力源模型，概括了一些神经病学 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，还增强了未来的阿片类药物背景学习。这种压力源模型和阿片类药物背景学习都是 依赖于基底外侧杏仁核（BLA）活性。应激可增强海马神经元的兴奋性和可塑性， BLA，导致了一种有趣的可能性，即严重的压力从根本上改变了学习过程， BLA，使个体更容易受到阿片类药物奖励学习的影响。使用一种新的活性依赖性标记 技术在大鼠模型中，该提议的第一个目的将检查神经元中是否存在显著的重叠 由严重的压力和吗啡情境配对激活。这些发现将为神经元 对严重压力的反应直接参与未来的阿片奖励线索学习。本建议的第二个目的是 将研究压力反应神经元是否是压力增强阿片类学习所必需的。这项工作将 促进跨学科的培训经验，包括复杂的行为方法的组合 与体内化学遗传学、体内活性依赖性标记和离体分析技术配对， 最终拓宽我们对创伤压力如何导致OUD发展的理解。这些 实验将在加州大学洛杉矶分校进行，这是一个优秀的培训环境，优先考虑生产力， 指导和协作，确保项目的成功。