Sciatic Nerve Stimulation Mitigates Depression‐Like Behaviors and Memory Deficits in Stressed Mice

Stress causes depression and cognitive decline. With limitations in pharmacotherapy, sciatic nerve stimulation (SNS) offers a promising nondrug alternative. This study aimed to explore the therapeutic efficacy of SNS in mitigating stress-induced depressive behaviors and memory deficits by focusing on astrocytic dysfunction and cellular senescence in the hippocampus. C57BL/6 mice were subjected to the water immersion restraint stress (WIRS) paradigm to induce stress-related behavioral deficits. Behavioral tests assessed locomotion, anxiety, depression-like behavior, and memory. Astrocytic disruption and cellular senescence in the hippocampus were assessed using glial fibrillary acidic protein (GFAP) immunostaining and senescence-associated β-galactosidase (SA-β-gal) staining. SNS at 20 Hz significantly improved cognitive function and reduced depression-like behavior in WIRS-treated mice. It also restored hippocampal GFAP expression and decreased both SA-β-gal-positive cell accumulation and the expression of senescence markers p16 and p21, suggesting an attenuation of cellular senescence. To further explore the link between cellular senescence and SNS-mediated effects, we administered the anti-senescence agent vitamin C to WIRS mice. While vitamin C alleviated stress-induced hippocampal senescence and depressive behavior, it failed to reverse memory deficits or restore GFAP expression, indicating that the benefits of SNS extend beyond its anti-senescent actions. In summary, SNS effectively counteracts the neurobehavioral consequences of chronic stress by targeting astrocytic dysfunction and cellular senescence. These findings support SNS as a promising, nonpharmacological strategy for treating stress-related depression and cognitive decline. Future studies should explore its clinical translation and broader therapeutic potential.