单次延长应激诱导创伤后应激障碍共病抑郁的免疫炎性机理
文献类型：学位论文
| 作者 | 戴佳婕 |
| 答辩日期 | 2023-06 |
| 文献子类 | 硕士 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 中国科学院心理研究所 |
| 其他责任者 | 王玮文 |
| 关键词 | 单次延长应激 创伤后应激障碍 抑郁 共病 免疫炎性 |
| 学位名称 | 理学硕士 |
| 学位专业 | 健康心理学 |
| 其他题名 | Inflammatory Mechanisms in Post-Traumatic Stress Disorder and Depression Comorbiditv Induced by Single Prolonged Stress |
| 中文摘要 | Objectives: Traumatic events can result in a range of traumatic stress spectrum disorders, among which post-traumatic stress disorder (PTSD) and major depression (MDD) are common complex syndromes after trauma exposure. Studies have shown that PTSD and MDD are highly co-morbid and have specific clinical features and pathophysiological changes that differ from other disease patterns, suggesting that there may be specific neurobiological basis for their comorbidity. Widespread immune inflammatory alterations are prevalent in traumatic stress spectrum disorders, but the immune cellular and molecular mechanisms underlying the comorbidity of PTSD and depression are currently unknown. This study aimed to investigate the effects of traumatic stress and pharmacological interventions on the comorbidity of PTSD and depression, and to further investigate the immune inflammatory mechanisms underlying their comorbidity. Methods: A modified single prolonged stress paradigm (SPS combined with foot shock, SPS&S) was used to establish a traumatic stress rat model to investigate: (1) the developmental change of PTSD-like and depressive-like behaviors in rats after traumatic stress. Depression-like behaviors were assessed using the sucrose preference test, the open field test, the tail suspension test, and the forced swimming test. The conditioned fear memory paradigm was used to assess PTSD-like behaviors, including spontaneous and evoked fear memory extinction deficits as well as anxious arousal. (2) At the time points when depression-like and PTSD-like behaviors changed significantly and simultaneously after traumatic stress, a stable co-morbid animal model was repeatedly established, and the correlation relationship between depression-like and PTSD-like behaviors was further investigated to confirm whether traumatic stress had a common effect on both. (3) the effects of chronic pharmacological intervention on co-expression of depression-like and PTSD-like behaviors in animals after traumatic stress was investigated by using paroxetine, a widely used clinical antidepressant and PTSD treatment drug. (4) the effects of chronic paroxetine intervention on changes of central and peripheral immune cells and inflammatory molecules induced by traumatic stress. Western blot was used to detect molecular changes related to the activation of microglia, a major kind of immunoreactive neural cell, including functional activation state molecule CD1lb and inflammatory response molecule CD68 in several emotion-related brain regions including medial prefrontal cortex, nucleus accumbens, amygdala and hippocampus; Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma levels of stress hormone corticosterone and inflammatory molecules including IL-6, IL-1β，TNF一a and CRP. Results: 1) SPS&S induced developmental changes in PTSD-like and depression-like behaviors in rats. The rats exhibited depression-like behaviors such as obvious anhedonia and behavioral helplessness in the early post-stress period (0-1 week). These behaviors continued to be evident in the middle post-stress period (2一3 weeks) and disappeared in the late post-stress period (4-5 weeks). The rats showed obvious anxiety-like and PTSD-like behaviors, including spontaneous fear memory extinction deficits and evoked fear memory extinction deficits, as well as anxious arousal, both in the middle and late post-stress periods, suggesting that significant PTSD-like and depressive-like behavioral phenotypes were induced simultaneously in the middle period (2一3 weeks) after SPS&S. 2) Repeatedly constructed traumatic stress model SPS&S, stably induced co-expression of depression-like and PTSD-like behaviors in the second week after traumatic exposure, and there was a significant positive correlation between them, suggesting a common effect of traumatic stress on the occurrence of PTSD-like and depression-like behaviors. 3) Chronic intervention with Serotonin reuptake inhibitor Paroxetine was able to ameliorate or restore co-expression of some depression-like and PTSD-like behaviors induced by SPS&S suggesting a common neurobiological basis for intervention effects on co-morbid behaviors. 4) SPS&S induced activation of microglia in emotion-related brain regions, mainly manifested by a significant increase in CDllb, a marker of microglia activation in the nucleus accumbens, amygdala and hippocampal brain regions, as well as a significant increase in the expression levels of CD68, a marker of inflammatory activation of microglia in hippocampus. Stress also resulted in significantly higher concentrations of peripheral plasma corticosterone and several inflammatory molecules such as TNF一a, IL-6, and CRP. Paroxetine intervention significantly reduced or reversed the stress-induced increase in most of the above central and peripheral immune inflammatory molecules. Conclusion: Through systematic experimental evidence at three levels of behavioral phenotype, immune inflammation and pharmacological intervention, this study demonstrates that SPS&S can be used to establish animal models of PTSD-like and depression-like behavioral comorbidity. Based on comorbid animal models, the role of immune inflammation in comorbidities was preliminarily discussed, which provided evidence support for further research on immune intervention strategies for the comorbidity of PTSD and depression. |
| 英文摘要 | 目的:创伤应激事件会诱发一系列创伤应激谱系障碍，其中创伤后应激障碍Cpost-traumatic stress disorder, PTSD)与重性抑郁障碍(major depression disorder,MDD)是创伤应激后常见的复杂综合征。已有研究表明PTSD与MDD间高度共病，且具有特定的临床特征及与其他疾病模式不同的病理生理改变，提示其共病可能存在特定的神经生物学基础。创伤应激谱系障碍普遍存在广泛的免疫炎性改变，但目前对于PTSD与MDD共病的免疫细胞和分子机理尚不清楚。本研究旨在调查创伤应激与药物干预对PTSD与MDD共病性的影响，并进一步探究两者共病的免疫炎性分子机制。 方法:采用单次延长应激结合足底电击范式(Single prolonged stress & Shock,SPS&S )建立创伤应激大鼠模型，探讨:(1)创伤应激后大鼠PTSD样与抑郁样行为的发展变化过程。采用糖水偏好测试、旷场测试、悬尾测试、强迫游泳测试评估抑郁样行为。采用条件性恐惧记忆范式评估PTSD样自发和诱发恐惧记忆消退缺陷以及焦虑性唤醒。(2)在创伤应激后抑郁样与PTSD样行为同时明显变化的时间点，重复建构稳定的共病动物模型，进一步分析抑郁样与PTSD样行为间的关系，以观察创伤应激是否对二者产生共同的影响。(3)采用临床广泛使用的抗抑郁和PTSD治疗药物帕罗西汀，观察慢性药物干预对于创伤应激后动物抑郁样行为及PTSD样行为共表达的影响。(4)抗抑郁药物干预对创伤应激诱导的中枢和外周免疫炎性分子的影响。采用蛋白免疫印迹方法(Western Blot)检测情绪相关脑区包括内侧前额叶、伏隔核、杏仁核和海马主要免疫反应细胞小胶质细胞激活相关分子的变化，包括功能活化状态分子CDllb和炎性反应分子CD68;采用酶联免疫吸附方法(ELISA)测定血浆中应激激素皮质酮以及炎性反应相关分子IL-6, IL-1β、TNF-a, CRP的改变。 结果:1) SPS&S诱发了大鼠PTSD样和抑郁样行为的发展性改变。表现为应激后早期(0-1周)大鼠表现出明显的快感缺失、行为无助等抑郁样行为。上述行为在应激后中期(2-3周)持续表现，而在后期(4-5周)消失。在应激后中期和后期大鼠均表现出明显的焦虑样和PTSD样行为，包括自发恐惧记忆消退缺陷和诱发恐惧记忆消退缺陷以及焦虑性唤醒，表明在SPS&S后中期(2-3周)同时诱导了明显的PTSD样和抑郁样行为表型。2)重复构建SPS&S应激模型，在创伤应激后第二周稳定诱发了抑郁样及PTSD样行为的显著改变，进一步相关分析显示两者之间存在显著的正相关，提示SPS&S可用于建立PTSD样与抑郁样行为共表达的模型。3)五经色胺重摄取抑制剂帕罗西汀药物慢性干预改善或恢复了SPS&S应激诱发的某些抑郁样和PTSD样行为的共同改变，提示药物对共病行为的干预效应具有共同的神经生物学基础。4 ) SPS&S应激诱发情绪相关脑区小胶质细胞激活，主要表现为伏隔核、杏仁核和海马脑区小胶质细胞活化标志物CDllb显著升高，同时海马小胶质细胞炎性激活标志物CD68表达水平也显著上升。应激还导致外周血浆皮质酮和多个炎性分子TNF-a, IL-6, CRP的浓度水平显著升高。而帕罗西汀干预显著降低或逆转了应激诱导的上述中枢和外周大多数免疫炎性分子表达的增加。 结论:sPS&s可以用于构建PTSD样与抑郁样行为共表达的动物模型，且从行为表型、免疫炎性和药物干预三个层面证实了该模型具有良好的效度，并且进一步基于共病动物模型对免疫炎性在共病中的作用进行了初步探讨，为进一步研究PTSD与抑郁共病的免疫干预策略提供了证据支持。 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/46083]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 推荐引用方式 GB/T 7714 | 戴佳婕. 单次延长应激诱导创伤后应激障碍共病抑郁的免疫炎性机理[D]. 中国科学院心理研究所. 中国科学院大学. 2023. |
入库方式： OAI收割
来源：心理研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。