Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post-traumatic stress disorder. Mus musculus

A social-stress mouse model, involving exposure of an intruder (male C57BL/6) mouse to a resident aggressor (male SJL) mouse followed by exposure to trauma reminders with post-trauma periods, was used to simulate features of human PTSD. Transcriptome changes in blood, brain regions and spleen, and DNA methylome changes in hemi-brain of aggressor-exposed and control C57BL/6 mice were assayed at one, 10 and 42 days of post-trauma periods. Assessments of activation patterns for differentially expressed transcripts (overlapping among hemi-brain, blood and spleen), and differentially methylated promoter regions showed increased activations of inflammatory pathways, and inhibited pathways related to neurogenesis and synaptic plasticity at longer post-trauma days. In amygdala, hippocampus and medial pre-frontal cortext, these pathways were activated at earlier post-trauma periods. But at longer post-trauma periods, neurogenesis and synaptic plasticity were inhibited while lower level of activated inflammation persisted in hippocampus and medial pre-frontal cortex. Pathways implicated in diabetes, insulin signaling, metabolic disorder, mitochondrial dysfunctions, circadian disruption, oxidative stress and inhibited telomere maintenance were significantly enriched. Identification of brain – blood overlapping molecular signatures provide increased confidence in using blood as brain surrogate sample for clinical translation. Our findings suggest that stress-induced inflammation triggers impaired neurogenesis, cognitive decline, and chronic pain (physical complaints in PTSD patients). Signaling pathways implicated in neurogenesis and synaptic plasticity seem to be mediating the effect of neuroinflammation in the development and maintenance of behavioral manifestations of PTSD. While inflammation seems to be directly involved in tissue damage triggering, exacerbating or maintaining the somatic comorbid pathologies of PTSD. Overall design: Transcriptome changes in blood, brain regions and spleen, and DNA methylome changes in hemi-brain of aggressor-exposed and control C57BL/6 mice were assayed at one, 10 and 42 days of post-trauma periods. This series includes the methylome data only. The transcriptome data was submitted previously and is available in GEO through series GSE45035.

本研究采用社交应激小鼠模型，通过将入侵者小鼠（雄性C57BL/6品系）暴露于常住攻击性小鼠（雄性SJL品系），随后辅以创伤提示刺激并设置创伤后观测周期，以此模拟人类创伤后应激障碍（Post-Traumatic Stress Disorder, PTSD）的核心特征。分别于创伤后第1、10、42天，对暴露于攻击性小鼠的小鼠与对照C57BL/6品系小鼠的血液、脑区及脾脏的转录组（transcriptome）变化，以及其半脑的DNA甲基化组（DNA methylome）变化进行检测。对重叠于半脑、血液与脾脏的差异表达转录本，以及差异甲基化启动子区域的激活模式进行分析后发现，在创伤后更长周期中，炎症通路（inflammatory pathways）激活程度升高，而与神经发生（neurogenesis）、突触可塑性（synaptic plasticity）相关的通路则受到抑制。在杏仁核（amygdala）、海马体（hippocampus）与内侧前额叶皮层（medial prefrontal cortex）中，这些通路在创伤后更早的周期即被激活。但在创伤后更长周期中，神经发生与突触可塑性受到抑制，而海马体与内侧前额叶皮层内的炎症激活水平仍维持在较低水平。与糖尿病、胰岛素信号通路、代谢紊乱、线粒体功能异常、昼夜节律紊乱、氧化应激以及端粒维持受抑制相关的通路均出现显著富集。脑-血液重叠分子特征的鉴定，提升了将血液作为脑替代样本用于临床转化（clinical translation）研究的可信度。本研究结果表明，应激诱导的炎症会引发神经发生受损、认知衰退以及慢性疼痛（即创伤后应激障碍患者的躯体不适症状）。参与神经发生与突触可塑性的信号通路，似乎在神经炎症（neuroinflammation）介导创伤后应激障碍行为表现（behavioral manifestations）的发生与维持过程中发挥调控作用。而炎症似乎直接参与了创伤后应激障碍躯体共病病理（somatic comorbid pathologies）的触发、加重或维持过程。实验整体设计：分别于创伤后第1、10、42天，检测暴露于攻击性小鼠的小鼠与对照C57BL/6品系小鼠的血液、脑区及脾脏的转录组变化，以及其半脑的DNA甲基化组变化。本数据集仅包含甲基化组数据，转录组数据已于此前提交，可通过基因表达综合数据库（Gene Expression Omnibus, GEO）的系列编号GSE45035获取。