Exercise-induced plasma-derived extracellular vesicles increase adult hippocampal neurogenesis

• Systemic ExerVs increased adult hippocampal neurogenesis in sedentary mice. • Systemic ExerVs did not significantly affect dentate gyrus vascular coverage. • ExerVs could protect against hippocampal atrophy, pending mechanistic insight. Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis. One candidate mechanism involves extracellular vesicles (EVs), lipid bilayer particles released during exercise that transport bioactive cargo to distant organs, including the brain. We tested whether plasma-derived EVs from exercising mice (ExerVs) are sufficient to promote hippocampal neurogenesis and vascular coverage in young, healthy sedentary mice. EVs were isolated from the plasma of sedentary or exercising C57BL/6J mice after four weeks of voluntary wheel running, collected during the dark phase, corresponding to peak running activity, and injected intraperitoneally into sedentary recipients twice weekly for four weeks. To evaluate reproducibility, the study was conducted across two independent cohorts using identical procedures. ExerV-treated mice showed an approximately 50 % increase in BrdU-positive cells in the granule cell layer relative to PBS- and SedV-treated controls in both cohorts. Approximately 89 % of these cells co-expressed NeuN, indicating neuronal differentiation, whereas 6 % co-expressed S100β, indicating astrocytic differentiation. No changes were observed in vascular areas across groups. These findings demonstrate that systemically delivered ExerVs are sufficient to enhance hippocampal neurogenesis but not vascular coverage. ExerVs may represent a promising therapeutic strategy for conditions marked by hippocampal atrophy, given their ability to enhance adult neurogenesis. Future studies are needed to elucidate the mechanisms linking peripheral ExerV administration to increased neurogenesis, and to determine whether this enhancement can restore cognitive function under conditions of hippocampal damage.