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Gut microbiota modulates synaptic plasticity, connectivity, and dopamine transmission in the VTA-mPFC pathway in bipolar depression

Molecular Psychiatry (2025)Cite this article

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Abstract

Adequate evidence has shown that gut microbial dysbiosis is an emerging disease phenotype of bipolar disorder (BD), and is closely related to clinical symptoms of this intractable disease. However, how gut microbiota affects the nervous system in BD remains largely unclear. In this study, we constructed a BD depression-like mouse model via fecal microbiota transplantation, and explored the changes of synaptic plasticity and connectivity in the medial prefrontal cortex (mPFC) of BD mice. We found that bipolar depression-like mice presented with a decrease in the density of dendritic spines in medial prefrontal neurons, and “Translation at postsynapse” as a key contributor to the changes in synaptic plasticity. In addition, analysis of synaptic connectivity in the mPFC revealed that compared to control mice, less connections were observed between ventral tegmental area and mPFC glutamate neurons and dopamine response was decreased in BD mice. These findings suggest that gut microbiota from BD depression patients induces the development of bipolar depression possibly by modulating aberrant synaptic connectivity and dopamine transmission in the VTA-mPFC pathway, which sheds light on the microbiota-gut-brain mechanisms underlying BD.

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Fig. 1: Colonization of gut microbiota from BD patients changes behavior and humanization of the microbiota in mice.
Fig. 2: Transcriptomic and dendritic spines changes in mPFC underlie BD-depression like behavior.
Fig. 3: Reduced dopamine space connections to mPFC neurons.
Fig. 4: Monosynaptic connections to BLA-projection mPFC neurons.
Fig. 5: Structural and functional dopamine deficiency of mPFC-projection VTA dopaminergic neurons.

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Data availability

All relevant data supporting the key findings of this study are available within the article and its Supplementary files.

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Acknowledgements

This study was funded by the National Key Research and Development Program of China (2023YFC2506200), STI 2030-Major Projects (2021ZD0200401), the National Natural Science Foundation of China (82571735,82471542,82201676), Key R&D Program of Zhejiang Province (2023C03077, 2024C03150, 2025C01119, 2024C03098, 2025C02109), the Fundamental Research Funds for the Central Universities.

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Author notes

  1. These authors contributed equally: Anying Tang, Yiwen Chen.

Authors and Affiliations

  1. State Key Laboratory of Extreme Photonics and Instrumentation & Liangzhu Laboratory, Department of Psychiatry of the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Anying Tang, Yiwen Chen, Ke Si, Jianbo Lai, Wei Gong & Shaohua Hu

  2. Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China

    Anying Tang, Wei Gong & Shaohua Hu

  3. NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, 310058, China

    Yiwen Chen, Ke Si, Jianbo Lai, Wei Gong & Shaohua Hu

  4. College of Optical Science and Engineering, Zhejiang University, Hangzhou, 310027, China

    Ke Si

  5. Research Units for Emotion and Emotion Disorders, Chinese Academy of Medical Sciences, Hangzhou, China

    Ke Si

  6. Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, 310003, China

    Jianbo Lai & Shaohua Hu

  7. Brain and Cognition Research Institute, School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Wei Gong

  8. Lingang Laboratory, Shanghai, 200031, China

    Wei Gong

  9. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Wei Gong

  10. The Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou, 310003, China

    Shaohua Hu

  11. The State Key Lab of Brain-Machine Intelligence, Zhejiang University, Hangzhou, 310003, China

    Shaohua Hu

  12. Brain Research, Institute of Zhejiang University, Hangzhou, 310003, China

    Shaohua Hu

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  1. Anying Tang
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  3. Ke Si
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  5. Wei Gong
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Contributions

SH Hu, W.Gong, JB Lai, K Si were responsible for the overall experimental design. YW Chen performed mice experiments, Stereotaxic injections, Tissue processing, Image acquisition and data analysis. AY Tang performed the mice experiments, fecal sample collect and mice behavior test data analysis. All the authors discussed the results and wrote the manuscript.

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Correspondence to Ke Si, Jianbo Lai, Wei Gong or Shaohua Hu.

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Tang, A., Chen, Y., Si, K. et al. Gut microbiota modulates synaptic plasticity, connectivity, and dopamine transmission in the VTA-mPFC pathway in bipolar depression. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03398-y

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