Aerobic exercise prevents neuroinflammation and ameliorates depressive-like behaviors via suppression of HMGB1/NF-κB pathway-mediated reactive microglial states in mice exposed to chronic mild stress

Aerobic exercise is shown to have a positive effect on depressive-like symptoms; however, the associated mechanisms have not yet been fully elucidated. The role of neuroinflammation in the pathogenesis of depression is well-documented. High mobility group box 1 (HMGB1), a late mediator of inflammation, can promote the release of pro-inflammatory cytokines in various inflammation-related diseases.

This study aimed to investigate the antidepressant effects of aerobic exercise by regulating hippocampal neuroinflammation via the HMGB1/NF-κB pathway-mediated microglial reactivity state. We assessed the depressive-like behaviors of the mice through behavioral tests. It was found that aerobic exercise significantly alleviated chronic mild stress (CMS)-induced depressive-like behaviors in mice.

Furthermore, aerobic exercise reduced the total number of microglia and altered microglial morphology and reactive states in the hippocampus, accompanied by down-regulation of pro-inflammatory markers. These effects were observed to be regulated by HMGB1. We found a significant nuclear-to-cytoplasmic translocation of HMGB1 in the hippocampus, in the absence of apoptotic alterations (pyknotic nuclei, karyorrhexis, karyolysis), indicating an active release in the brain after CMS stimulation.

Interestingly, aerobic exercise could reverse these alterations by inhibiting the HMGB1/NF-κB pathway. These findings not only enhance the understanding of the processes driving neuroinflammation in the hippocampi of mice exposed to CMS, but also highlight the potential of aerobic exercise as an anti-depression therapeutic strategy. The authors thank all the staff in the Laboratory Animal Center, Southwest Medical University, People’s Republic of China, for providing assistance with the study.

This work was supported by Natural Science Foundation of Sichuan Province (2025ZNSFSC1564), Science and Technology Plan Program of Luzhou (Applied Basic Research Project) (2024JYJ011), National Natural Science Foundation of China (82602953). These authors contributed equally: Lirong Jiang, Chaofan Zhang. Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China Lirong Jiang, Chaofan Zhang, Debo Yang, Song Liu, Ruiyi Liao, Enhao Xu, Yang Yu & Li Liu Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China The authors declare no competing interest.

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