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.