He Zhen, Qin Yihan, Xie Guanbo, Li Fei, Wu Ning
School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China; Beijing Institute of Pharmacology and Toxicology, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China.
Beijing Institute of Pharmacology and Toxicology, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China.
Biochem Biophys Res Commun. 2025 Aug 30;776:152205. doi: 10.1016/j.bbrc.2025.152205. Epub 2025 Jun 13.
Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder characterized by re-experiencing, avoidance of trauma-related stimuli, negative changes in mood and cognition, and hyperarousal. Despite its prevalence, the pathogenesis and molecular mechanisms underlying PTSD remain poorly understood. In the present study, a mouse model simulating PTSD was established through a modified single prolonged stress (SPS) in conjunction with plantar shock (SPS+shock). Contextual fear-like and active avoidance behaviors were assessed using the contextual freezing test and the cue avoidance test, respectively. Four weeks after stress exposure, the SPS+shock mice were categorized into PTSD-like (+) (exhibiting PTSD-like behavioral phenotype) and PTSD-like (-) (lacking the behavioral phenotype) groups. Hippocampal gene expression profiles were obtained through high-throughput RNA sequencing (RNA-seq). Functional enrichment analysis of significantly differentially expressed genes revealed pathways associated with the PTSD-like (+) phenotype, including the Notch signaling pathway and GABAergic synapse. Using the CytoHubba plugin, three hub genes enriched in the Notch signaling pathway and three hub genes enriched in the GABAergic synapse were identified. Additionally, weighted gene co-expression network analysis highlighted key pathways, including the Notch signaling pathway, ATP-dependent chromatin remodeling, histone modification and mitochondrial oxidative phosphorylation. Within these pathways, 16 hub genes were screened out. Additionally, the mRNA expression changes of nine hub genes validated by qPCR, showed similar trends to the RNA-seq data. Collectively, our results found important biological pathways and hub genes associated with the PTSD-like behavioral phenotype in mice, offering potential insights into the pathological mechanisms of PTSD and identifying novel therapeutic targets.
创伤后应激障碍（PTSD）是一种与创伤和应激源相关的障碍，其特征为创伤重现、回避与创伤相关的刺激、情绪和认知的消极变化以及过度警觉。尽管其患病率较高，但PTSD的发病机制和分子机制仍知之甚少。在本研究中，通过改良的单次长时间应激（SPS）结合足底电击（SPS+电击）建立了模拟PTSD的小鼠模型。分别使用情境性僵住试验和线索回避试验评估情境性恐惧样行为和主动回避行为。应激暴露四周后，将SPS+电击小鼠分为PTSD样（+）组（表现出PTSD样行为表型）和PTSD样（-）组（缺乏行为表型）。通过高通量RNA测序（RNA-seq）获得海马基因表达谱。对显著差异表达基因的功能富集分析揭示了与PTSD样（+）表型相关的通路，包括Notch信号通路和GABA能突触。使用CytoHubba插件，鉴定出在Notch信号通路中富集的三个枢纽基因和在GABA能突触中富集的三个枢纽基因。此外，加权基因共表达网络分析突出了关键通路，包括Notch信号通路、ATP依赖的染色质重塑、组蛋白修饰和线粒体氧化磷酸化。在这些通路中，筛选出16个枢纽基因。此外，通过qPCR验证的9个枢纽基因的mRNA表达变化与RNA-seq数据显示出相似的趋势。总体而言，我们的结果发现了与小鼠PTSD样行为表型相关的重要生物学通路和枢纽基因，为PTSD的病理机制提供了潜在的见解，并确定了新的治疗靶点。
