Hippocampal transcriptome profiling associated with post-traumatic stress disorder-like behaviors in male mice

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.