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: 10315181
• 负责人: Jamie Elizabeth Mondello
• 金额: $ 4.05万
• 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/10315181
• 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/文摘