Transcutaneous auricular vagus nerve stimulation improves emotional and cognitive functions in post-traumatic stress disorder rats through anti-inflammation, neuroprotection, and modulation of the hippocampal nuclear factor erythroid 2-related factor 2-heme oxygenase-1-glutathione peroxidase 4 pathway.

Abstract

Objective: To investigate the role and potential molecular mechanisms of transcutaneous auricular vagus nerve stimulation (taVNS) in post-traumatic stress disorder (PTSD).

Methods: A single prolonged stress (SPS) model of PTSD was used to conduct behavioral tests and evaluate the effects of taVNS on the emotion-cognitive function in PTSD animals. Focusing on the prefrontal cortex-hippocampus brain region, we systematically evaluated the growth status of neurons and astrocytes, as well as the level of microglial-mediated neuroinflammation. Key indicators of the nuclear factor erythroid 2-related (NRF2)-heme oxygenase-1 (HO-1)-glutathione peroxidase 4 (GPX4) signaling pathway were detected and analyzed. Additionally, immune and oxidative stress levels in peripheral plasma were also assessed.

Results: Two weeks of taVNS significantly improved the abnormal emotion-cognitive function in PTSD animals and partially inhibited peripheral oxidative stress injury and immune-inflammatory responses. Compared with the prefrontal cortex, taVNS markedly alleviated hippocampal neuron loss, microglial activation, and astrocyte dysfunction in PTSD rats, suggesting that the NRF2-HO-1-GPX4 signaling pathway may play a critical role in this process.

Conclusion: taVNS extensively modulates the functions of neurons and glial cells by regulating both central and peripheral oxidative stress and immune-inflammatory responses, thereby ameliorating the abnormal emotional and cognitive functions observed in PTSD animals.