Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress

Molecular Psychiatry (2024)Cite this article

Subjects

Abstract

Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Running exercise alleviates depressive-like behaviors in mice exposed to CUS and alters pro- and anti-inflammatory cytokine expression in the hippocampus of CUS model mice.
Fig. 2: Running exercise decreased the number of microglia and altered microglial morphology in subfields of the hippocampus in CUS model mice.
Fig. 3: Running exercise regulated the balance of microglial M1/M2 polarization in the hippocampus of CUS model mice.
Fig. 4: Running exercise increased the expression of adiponectin in muscle and eWAT, elevated adiponectin concentrations in the plasma, and activated the adiponectin/AdipoR1 signaling pathway in the hippocampus of CUS model mice.
Fig. 5: Hippocampal AdipoR1 knockdown induced depressive-like behaviors in mice and an imbalance between M1 and M2 polarization and a neuroinflammatory response in the hippocampus of mice.
Fig. 6: Changes in the number of microglia and microglial morphology in subfields of the hippocampus in AdipoR1 KD mice.

Similar content being viewed by others

Data availability

The datasets acquired for this study are available from the corresponding author upon reasonable request.

References

  1. Smith K. Mental health: a world of depression. Nature. 2014;515:181.

    Article  PubMed  ADS  Google Scholar 

  2. Malhi GS, Mann JJ. Depression. Lancet. 2018;392:2299–312.

    Article  PubMed  Google Scholar 

  3. Rimer J, Dwan K, Lawlor DA, Greig CA, McMurdo M, Morley W, et al. Exercise for depression. Cochrane Database Syst Rev. 2012;7:CD004366.

  4. Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of exercise: a meta-analysis of randomized trials. Sports Med. 2009;39:491–511.

    Article  PubMed  Google Scholar 

  5. Gujral S, Aizenstein H, Reynolds CF, Butters MA, Erickson KI. Exercise effects on depression: possible neural mechanisms. Gen Hosp Psychiatry. 2017;49:2–10.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Xiao K, Luo Y, Liang X, Tang J, Wang J, Xiao Q, et al. Beneficial effects of running exercise on hippocampal microglia and neuroinflammation in chronic unpredictable stress-induced depression model rats. Transl Psychiatry. 2021;11:461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tang J, Liang X, Dou X, Qi Y, Yang C, Luo Y, et al. Exercise rather than fluoxetine promotes oligodendrocyte differentiation and myelination in the hippocampus in a male mouse model of depression. Transl Psychiatry. 2021;11:622.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li Y, Luo Y, Tang J, Liang X, Wang J, Xiao Q, et al. The positive effects of running exercise on hippocampal astrocytes in a rat model of depression. Transl Psychiatry. 2021;11:83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Huang D, Xiao Q, Tang J, Liang X, Wang J, Hu M, et al. Positive effects of running exercise on astrocytes in the medial prefrontal cortex in an animal model of depression. J Comp Neurol. 2022;530:3056–71.

    Article  PubMed  Google Scholar 

  10. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021;18:258.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Garaschuk O, Verkhratsky A. Physiology of microglia. Methods Mol Biol. 2019;2034:27–40.

    Article  CAS  PubMed  Google Scholar 

  13. Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649–65.

    Article  CAS  PubMed  Google Scholar 

  14. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015;11:56–64.

    Article  PubMed  Google Scholar 

  15. Zhang L, Zhang J, You Z. Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front Cell Neurosci. 2018;12:306.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  16. Spielman LJ, Little JP, Klegeris A. Physical activity and exercise attenuate neuroinflammation in neurological diseases. Brain Res Bull. 2016;125:19–29.

    Article  CAS  PubMed  Google Scholar 

  17. Liu W, Ge T, Leng Y, Pan Z, Fan J, Yang W, et al. The role of neural plasticity in depression: from hippocampus to prefrontal cortex. Neural Plast. 2017;2017:6871089.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fang H, Judd RL. Adiponectin regulation and function. Compr Physiol. 2018;8:1031–63.

    Article  PubMed  Google Scholar 

  19. Bloemer J, Pinky PD, Govindarajulu M, Hong H, Judd R, Amin RH, et al. Role of adiponectin in central nervous system disorders. Neural Plast. 2018;2018:4593530.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Leo R, Di Lorenzo G, Tesauro M, Cola C, Fortuna E, Zanasi M, et al. Decreased plasma adiponectin concentration in major depression. Neurosci Lett. 2006;407:211–3.

    Article  CAS  PubMed  Google Scholar 

  21. Narita K, Murata T, Takahashi T, Kosaka H, Omata N, Wada Y. Plasma levels of adiponectin and tumor necrosis factor-alpha in patients with remitted major depression receiving long-term maintenance antidepressant therapy. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1159–62.

    Article  CAS  PubMed  Google Scholar 

  22. Yau SY, Li A, Hoo RLC, Ching YP, Christie BR, Lee TMC, et al. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc Natl Acad Sci USA. 2014;111:15810–5.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  23. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332–9.

    Article  CAS  PubMed  Google Scholar 

  24. Thundyil J, Pavlovski D, Sobey CG, Arumugam TV. Adiponectin receptor signalling in the brain. Br J Pharmacol. 2012;165:313–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao L, Chen S, Sherchan P, Ding Y, Zhao W, Guo Z, et al. Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice. J Neuroinflammation. 2018;15:215.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Song J, Choi SM, Kim BC. Adiponectin regulates the polarization and function of microglia via ppar-gamma signaling under amyloid beta toxicity. Front Cell Neurosci. 2017;11:64.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu Y, Chewchuk S, Lavigne C, Brûlé S, Pilon G, Houde V, et al. Functional significance of skeletal muscle adiponectin production, changes in animal models of obesity and diabetes, and regulation by rosiglitazone treatment. Am J Physiol Endocrinol Metab. 2009;297:E657–E664.

    Article  CAS  PubMed  Google Scholar 

  28. Eyre H, Baune BT. Neuroimmunological effects of physical exercise in depression. Brain Behav Immun. 2012;26:251–66.

    Article  CAS  PubMed  Google Scholar 

  29. Kohler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381–91.

    Article  PubMed  Google Scholar 

  30. Karperien A, Ahammer H, Jelinek HF. Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci. 2013;7:3.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Morrison H, Young K, Qureshi M, Rowe RK, Lifshitz J. Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury. Sci Rep. 2017;7:13211.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  32. Zhang J, Xie X, Tang M, Zhang J, Zhang B, Zhao Q, et al. Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stress-exposed mice. Brain Behav Immun. 2017;66:111–24.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang L, Tang M, Xie X, Zhao Q, Hu N, He H, et al. Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARgamma activation in male mice exposed to chronic mild stress. J Neuroinflammation. 2021;18:171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999;96:13427–31.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  35. Gong H, Tai H, Huang N, Xiao P, Mo C, Wang X, et al. Nrf2-SHP cascade-mediated STAT3 inactivation contributes to AMPK-driven protection against endotoxic inflammation. Front Immunol. 2020;11:414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guo S, Wang H, Yin Y. Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci. 2022;14:815347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen S, Dong Z, Cheng M, Zhao Y, Wang M, Sai N, et al. Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke. J Neuroinflammation. 2017;14:187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank all the staff in the Laboratory Animal Center, Chongqing Medical University, People’s Republic of China, for providing assistance with the study.

Funding

This work was supported by National Natural Science Foundation of China (82171522, 82001436, 81871073, 82001435), Natural Science Foundation of Chongqing, China (cstc2021jcyj-msxmX0110), and Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN202000402).

Author information

Authors and Affiliations

  1. Department of Histology and Embryology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Li Liu, Jing Tang, Yue Li, Peilin Zhu, Mei Zhou, Lu Qin, Yuhui Deng, Jing Li, Yiying Wang, Dujuan Huang, Yuning Zhou, Shun Wang & Yong Tang

  2. Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Li Liu, Jing Tang, Yue Li, Peilin Zhu, Lu Qin, Yuhui Deng, Jing Li, Yiying Wang, Dujuan Huang, Yuning Zhou, Shun Wang, Yanmin Luo & Yong Tang

  3. Department of Pathology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Xin Liang

  4. Department of Physiology, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Mei Zhou & Yanmin Luo

  5. Lab Teaching & Management Center, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Lin Jiang

  6. Department of Radioactive Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Qian Xiao

Authors
  1. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peilin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lu Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuhui Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yiying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dujuan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yuning Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Qian Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yanmin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yong Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL participated in the design, research, and data analysis and wrote the draft manuscript. YML, JT, and XL guided the experiments and provided technical assistance. YYW provided technical assistance. YL, PLZ, MZ, LQ, YHD, JL, LJ, DJH, and QX conducted the animal experiments. YYW, MZ, YNZ, and SW assisted in the confocal fluorescence microscopy scans. YML reviewed and revised the manuscript. YML and YT helped with the experimental design, supervised the overall project, and revised the manuscript.

Corresponding authors

Correspondence to Yanmin Luo or Yong Tang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, L., Tang, J., Liang, X. et al. Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02464-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-024-02464-1

Search

Advanced search

Quick links