Abstract
Exercise training effectively relieves anxiety disorders via modulating specific brain networks. The role of post-translational modification of proteins in this process, however, has been underappreciated. Here we performed a mouse study in which chronic restraint stress-induced anxiety-like behaviors can be attenuated by 14-day persistent treadmill exercise, in association with dramatic changes of protein phosphorylation patterns in the medial prefrontal cortex (mPFC). In particular, exercise was proposed to modulate the phosphorylation of Nogo-A protein, which drives the ras homolog family member A (RhoA)/ Rho-associated coiled-coil-containing protein kinases 1(ROCK1) signaling cascade. Further mechanistic studies found that liver-derived kynurenic acid (KYNA) can affect the kynurenine metabolism within the mPFC, to modulate this RhoA/ROCK1 pathway for conferring stress resilience. In sum, we proposed that circulating KYNA might mediate stress-induced anxiety-like behaviors via protein phosphorylation modification within the mPFC, and these findings shed more insights for the liver-brain communications in responding to both stress and physical exercise.
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Acknowledgements
We thank Dr. Run-hua Wang (The Affiliated Brain Hospital of Guangzhou Medical University) for the help in collecting human blood samples. This work was funded by STI2030-Major Projects (2022ZD0207600) to LZ, National Key Research and Development Program of China (2020YFA0113600) to LZ, National Natural Science Foundation of China (U22A20301 to KFS, 32070955 to LZ), Key Research and Development Plan of Ningxia (2022BEG01004) to KFS, and Guangdong Basic and Applied Basic Research Foundation (2023B1515040015) to LZ.
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Conceptualization, LY and LZ; Methodology, LY, WJW, TC and LZ; Validation, LY and LZ; Formal analysis, LY, WW and TC; Investigation, LY, WJW, TC, Yang-ze Wang, DRY, Ya-jie Wang, and FZY; Resources, WJW, DRY. and FZY. Data Curation, LY and LZ; Writing - Original Draft, LZ and LY; Writing – Review & Editing, WJW, LZ and KFS; Visualization, LY and LZ; Supervision, KFS and LZ; Project Administration, LZ and KFS; Funding Acquisition, LZ and KFS.
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Yan, L., Wang, Wj., Cheng, T. et al. Hepatic kynurenic acid mediates phosphorylation of Nogo-A in the medial prefrontal cortex to regulate chronic stress-induced anxiety-like behaviors in mice. Acta Pharmacol Sin 45, 2032–2044 (2024). https://doi.org/10.1038/s41401-024-01302-y
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DOI: https://doi.org/10.1038/s41401-024-01302-y
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