Proteomic analysis of transcutaneous auricular vagus nerve stimulation induced cognitive restoration in a mouse model of vascular cognitive impairment

Abstract Vascular cognitive impairment (VCI) is a major cause of dementia with limited treatment options. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulation approach that has shown cognitive benefits, but its molecular basis remains unclear. Here, we employed a mouse model of transient bilateral common carotid artery occlusion (tBCCAO) to identify molecular candidates underlying the cognitive restorative effects of taVNS. tBCCAO impaired cognitive function as revealed by behavioral assessments, whereas taVNS restored behavioral performance. Hippocampal proteomic analysis identified 58 proteins altered in tBCCAO compared with sham, and 16 proteins significantly modulated by taVNS compared with tBCCAO. Among these, a core set of taVNS-responsive proteins exhibited a normalization-like pattern, suggesting that taVNS shifted ischemia-associated proteomic alterations toward a near-normal state rather than simply amplifying or suppressing the overall response. These findings suggest that taVNS may improve VCI by restoring hippocampal protein dysregulation following transient cerebral hypoperfusion and highlight molecular targets as candidate mechanisms for further investigation.