HIF‐1α and HIF‐2α Are Upregulated in the Hippocampus but Not in the Medial Prefrontal Cortex in Experimental PTSD
Denys Porkhalo, Denis Pashevin, Yana Naumenko, Victor DosenkoABSTRACT
Background
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).
Methods
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.
Results
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.
Conclusions
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.