Transcutaneous auricular vagus nerve stimulation attenuates neuroinflammation in a mouse model of traumatic brain injury

INTRODUCTION – Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Although TBI pathophysiology has been thoroughly investigated, the effectivity of therapeutic approaches for TBI is still lacking. Our group has developed a novel approach of noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) in a mouse model of TBI to investigate its impact on neuroinflammation. METHODS – A murine-controlled cortical impact model was used, and results were analyzed on postinjury days (PIDs) 3 and 7. The experimental groups included (1) sham C57BL/6 wild type (WT), (2) TBI wild type, (3) sham-taVNS, and (4) TBI-taVNS. The animals underwent anesthesia, off-site stimulation, or taVNS for 30 minutes. The short- and long-term groups received two sessions of taVNS treatment and were tested on PIDs 3 and 7, respectively. A combination of real-time polymerase chain reaction and immunohistochemistry was used to validate the success of the model and to quantify gene expression associated with microglial and astrocyte activation. Student's t test and one-way analysis of variance were used for statistical analysis, with significance achieved when p < 0.05. RESULTS – Transcutaneous auricular vagus nerve stimulation (VNS) activated the solitary tract nucleus and the dorsal motor nucleus of the vagus nerve as evidenced by a significant upregulation of the neuronal activation marker c-Fos, indicating vagus nerve activation. Transcutaneous auricular VNS treatment reduced the expression of pro-inflammatory microglial markers Tnf (1.69 ± 0.17 vs. 3.615 ± 0.86, p < 0.05) and Lcn2 (64.15 ± 14 vs. 337.7 ± 104.8, p < 0.01) in the ipsilateral injured cortex on PIDs 3 and 7, respectively. Transcutaneous auricular VNS also increased the expression of anti-inflammatory microglial marker Arg1 (55 ± 6.47 vs. 30.49 ± 3.94, p < 0.01) and astrocyte Gfap reactivity (8, 582 ± 826 vs. 4, 569 ± 554.3, p < 0.01) on PID 3.