Title : Microglial H3K18la records the intergenerational effects of maternal exercise and triggers stress memory in offspring

Histone modifications serve as molecular mediators for the intergenerational inheritance of exercise-induced benefits, yet the underlying mechanisms remain elusive. Here, we demonstrate that maternal exercise during pregnancy enhances resilience to chronic restraint stress in adult offspring. This intergenerational protection is mediated by an amplified maternal-placental-fetal lactate supply, driven by the upregulation of placental monocarboxylate transporters (MCTs). Notably, this transient maternal signal induces a stable epigenetic imprint within the offspring’s hippocampus, characterized by elevated levels of histone H3 lysine 18 lactylation (H3K18la) in microglia. While this modification remains dormant under homeostatic conditions, it is recruited upon secondary stress challenge in adulthood to promote a restorative (M2-like) microglial polarization state and suppress neuroinflammation. Collectively, our study identifies a previously unrecognized lactylation-epigenetic axis that encodes maternal exercise effects into the offspring’s genome. This axis enhances offspring responsiveness to environmental challenges in adulthood through a mechanism akin to an “immune stress-priming and awakening” model.

Professor Weina Liu focuses on exercise health promotion and the physiological mechanisms of exercise interventions for depression. She has published over 60 papers in prominent journals, including PNAS, J Adv Res, and Brain Behav Immun, and authored two monographs Prof. Liu has led over 10 major grants, including National Social Science and Natural Science Funds. Additionally, she directs national top-tier courses, co-edited five textbooks, received multiple national and Shanghai academic awards, and serves on the editorial boards of several SCI/SSCI journals.