HIF-1α and HIF-2α Are Upregulated in the Hippocampus but Not in the Medial Prefrontal Cortex in Experimental PTSD

Post-traumatic stress disorder (PTSD) is a psychiatric disorder characterized by anxiety, abnormal stress responses, and pathological memory formation. Research indicates that hypoxia-inducible pathways might influence the neurobiology of PTSD. However, the specific relationship between hypoxia-inducible factors (HIFs), neuropeptides, and brain regions remains unclear. This study investigated behavioral and molecular alterations in a rat model of PTSD, with a particular focus on the expression of HIF-1α, HIF-2α, HIF-3α, PACAP, and PAI-1 in the hippocampus and medial prefrontal cortex (mPFC).

PTSD was modelled in adult male rats using the single prolonged stress (SPS) protocol, consisting of 2-h immobilization, 15-min forced swimming, and diethyl ether anesthesia. Behavioral assessment was performed 7 days post-SPS using the open field test, elevated plus maze (EPM), and dark-light box. Gene expression in the hippocampus and mPFC was quantified by RT-qPCR using the 2^(-ΔΔCt) method with β-actin as a reference gene.

SPS-exposed rats exhibited significant anxiety-like behavior. In the elevated plus maze, they showed increased freezing time (p = 0.0001), more freezing episodes (p = 0.002), fewer open-arm head dips (p = 0.002), reduced open-arm time (p = 0.027), and shorter total distance travelled (p = 0.026) compared to controls, whereas the reduction in open-arm entries did not reach significance (p = 0.051). In the dark-light box, PTSD animals made significantly fewer entries into the light zone (p = 0.009). No significant differences were detected in the open field test. At the molecular level, hippocampal HIF-1α and HIF-2α mRNA expression was significantly elevated in PTSD animals relative to controls (2.05- and 2.18-fold, respectively; p < 0.05). No significant changes were detected for HIF-3α, PACAP, or PAI-1 in either brain region. No significant differences in gene expression were found in the mPFC.

PTSD is associated with selective upregulation of HIF-1α and HIF-2α in the hippocampus, suggesting region-specific activation of hypoxia-inducible signaling pathways in the context of traumatic stress.