The Brain Science Center, Beijing Institute of Basic Medical Sciences, No. 27 Taiping Road, Haidian District, Beijing, 100850, China.
Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, 100081, China.
J Neuroinflammation. 2021 Jan 5;18(1):7. doi: 10.1186/s12974-020-02069-9.
Alteration of immune status in the central nervous system (CNS) has been implicated in the development of post-traumatic stress disorder (PTSD). However, the nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear.
We constructed a mouse PTSD model by electric foot-shocks followed by contextual reminders and verified the PTSD-related symptoms by behavior test (including contextual freezing test, open-field test, and elevated plus maze test). We examined the immunocyte panorama in the brains of the naïve or PTSD mice by using single-cell mass cytometry. Microglia number and morphological changes in the hippocampus, prefrontal cortex, and amygdala were analyzed by histopathological methods. The gene expression changes of those microglia were detected by quantitative real-time PCR. Genetic/pharmacological depletion of microglia or minocycline treatment before foot-shocks exposure was performed to study the role of microglia in PTSD development and progress.
We found microglia are the major brain immune cells that respond to PTSD. The number of microglia and ratio of microglia to immunocytes was significantly increased on the fifth day of foot-shock exposure. Furthermore, morphological analysis and gene expression profiling revealed temporal patterns of microglial activation in the hippocampus of the PTSD brains. Importantly, we found that genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure alleviated PTSD-associated anxiety and contextual fear.
Our results demonstrated a critical role for microglial activation in PTSD development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition.
中枢神经系统（CNS）免疫状态的改变与创伤后应激障碍（PTSD）的发生有关。然而，PTSD 状态下大脑免疫细胞景观的整体变化性质尚不清楚。
我们通过电脚刺激后进行情境提醒构建了 PTSD 小鼠模型，并通过行为测试（包括情境性冻结测试、旷场测试和高架十字迷宫测试）验证了与 PTSD 相关的症状。我们使用单细胞质量细胞术检查了未受刺激或 PTSD 小鼠大脑中的免疫细胞全景。通过组织病理学方法分析海马体、前额叶皮层和杏仁核中小胶质细胞数量和形态变化。通过定量实时 PCR 检测这些小胶质细胞的基因表达变化。在进行电击暴露之前进行小胶质细胞的基因/药物耗竭或米诺环素治疗，以研究小胶质细胞在 PTSD 发展和进展中的作用。
我们发现小胶质细胞是对 PTSD 有反应的主要大脑免疫细胞。在电击暴露的第五天，小胶质细胞的数量和小胶质细胞与免疫细胞的比例显著增加。此外，形态分析和基因表达谱分析显示 PTSD 大脑中海马体中小胶质细胞的激活具有时间模式。重要的是，我们发现小胶质细胞的基因/药物耗竭或米诺环素治疗在电击暴露前可以减轻 PTSD 相关的焦虑和情境性恐惧。
我们的结果表明小胶质细胞激活在 PTSD 发展中起关键作用，以小胶质细胞抑制为形式的临床治疗 PTSD 的潜在治疗策略。
