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bioRxiv · 10.1101/2025.08.02.668291

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

Connolly, M. G.·Fliflet, A. M.·Ravi, P.·Rosu, D. I.·Boppart, M. D.·Rhodes, J. S.
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Abstract

Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis, angiogenesis, and astrogliogenesis. Since hippocampal atrophy is a hallmark of several neurological and psychiatric conditions--including depression, PTSD, Alzheimers disease, and aging--understanding the mechanisms by which exercise increases neurogenesis has broad therapeutic relevance. One potential mechanism involves extracellular vesicles (EVs), lipid bilayer-enclosed particles released by multiple tissues during exercise that transport bioactive molecular cargo to distant organs, including the brain. In this study, we tested whether plasma-derived EVs from exercising mice (ExerVs) are sufficient to promote hippocampal neurogenesis, astrogliogenesis, and vascular density in sedentary mice. EVs were isolated from the plasma of sedentary or exercising C57BL/6J mice 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 a significant increase in BrdU-positive cells in the granule cell layer compared to both PBS- and SedV-treated controls in both cohorts. Approximately 90% of these cells co-expressed NeuN, indicating neuronal differentiation, while 6% co-expressed S100{beta}, indicating astrocyte generation. No changes were observed in vascular density across groups. These findings provide initial evidence that systemically delivered exercise-derived EVs can enhance hippocampal neurogenesis and astrogliogenesis in sedentary mice. This proof-of-concept work supports further investigation into ExerVs as a potential therapeutic strategy for conditions associated with hippocampal atrophy. HighlightsO_LIExerVs increase hippocampal neurogenesis and astrogliogenesis in sedentary mice C_LIO_LIExerVs do not affect hippocampal vascular area C_LIO_LICirculating ExerVs are sufficient to recapitulate key brain benefits of exercise C_LI

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Connolly, M. G., Fliflet, A. M., Ravi, P., Rosu, D. I., Boppart, M. D., Rhodes, J. S.. 2025-08-02. Exercise-induced plasma-derived extracellular vesicles increase adult hippocampal neurogenesis. https://doi.org/10.1101/2025.08.02.668291

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