Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model

Abstract

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.