IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56258-2.html
   My bibliography  Save this article

Treadmill exercise prevents stress-induced anxiety-like behaviors via enhancing the excitatory input from the primary motor cortex to the thalamocortical circuit

Author

Listed:
  • Zhihua Luo

    (Jinan University
    Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Junlin Chen

    (Jinan University)

  • Yuchu Liu

    (Jinan University)

  • Yelin Dai

    (Jinan University)

  • Hui Gao

    (Jinan University)

  • Borui Zhang

    (Jinan University)

  • Haibin Ou

    (Jinan University)

  • Kwok-Fai So

    (Jinan University
    The University of Hong Kong)

  • Ji-an Wei

    (Jinan University)

  • Li Zhang

    (Jinan University
    University of Health and Rehabilitation Sciences
    Shanghai University of Sport)

Abstract

Physical exercise effectively prevents anxiety disorders caused by environmental stress. The neural circuitry mechanism, however, remains incomplete. Here, we identified a previously unrecognized pathway originating from the primary motor cortex (M1) to medial prefrontal cortex (mPFC) via the ventromedial thalamic (VM) nuclei in male mice. Besides anatomical evidence, both ex vivo and in vivo recordings showed enhanced excitability of M1-VM inputs to the prelimbic (PrL) region of mPFC upon 14-day treadmill exercise on a chronic restraint stress (CRS) mouse model. Further functional interrogations demonstrated that the activation of this neural circuit is both necessary and sufficient to direct the anxiolytic effect of exercise training in CRS mice. Our findings provide more insights into the neural circuits connecting motor and mental regions under exercise paradigm and implicate potential targets for neuromodulation in treating anxiety disorders.

Suggested Citation

  • Zhihua Luo & Junlin Chen & Yuchu Liu & Yelin Dai & Hui Gao & Borui Zhang & Haibin Ou & Kwok-Fai So & Ji-an Wei & Li Zhang, 2025. "Treadmill exercise prevents stress-induced anxiety-like behaviors via enhancing the excitatory input from the primary motor cortex to the thalamocortical circuit," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56258-2
    DOI: 10.1038/s41467-025-56258-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56258-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56258-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jia-Ni Li & Xue-Mei Wu & Liu-Jie Zhao & Han-Xue Sun & Jie Hong & Feng-Ling Wu & Si-Hai Chen & Tao Chen & Hui Li & Yu-Lin Dong & Yun-Qing Li, 2023. "Central medial thalamic nucleus dynamically participates in acute itch sensation and chronic itch-induced anxiety-like behavior in male mice," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Avishek Adhikari & Talia N. Lerner & Joel Finkelstein & Sally Pak & Joshua H. Jennings & Thomas J. Davidson & Emily Ferenczi & Lisa A. Gunaydin & Julie J. Mirzabekov & Li Ye & Sung-Yon Kim & Anna Lei , 2015. "Basomedial amygdala mediates top-down control of anxiety and fear," Nature, Nature, vol. 527(7577), pages 179-185, November.
    3. Wei-Zhu Liu & Wen-Hua Zhang & Zhi-Heng Zheng & Jia-Xin Zou & Xiao-Xuan Liu & Shou-He Huang & Wen-Jie You & Ye He & Jun-Yu Zhang & Xiao-Dong Wang & Bing-Xing Pan, 2020. "Identification of a prefrontal cortex-to-amygdala pathway for chronic stress-induced anxiety," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    4. Guo-Qiang Wang & Cheng Cen & Chong Li & Shuai Cao & Ning Wang & Zheng Zhou & Xue-Mei Liu & Yu Xu & Na-Xi Tian & Ying Zhang & Jun Wang & Li-Ping Wang & Yun Wang, 2015. "Deactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    5. Jason S. Snyder & Amélie Soumier & Michelle Brewer & James Pickel & Heather A. Cameron, 2011. "Adult hippocampal neurogenesis buffers stress responses and depressive behaviour," Nature, Nature, vol. 476(7361), pages 458-461, August.
    6. D. S. Engelke & X. O. Zhang & J. J. O’Malley & J. A. Fernandez-Leon & S. Li & G. J. Kirouac & M. Beierlein & F. H. Do-Monte, 2021. "A hypothalamic-thalamostriatal circuit that controls approach-avoidance conflict in rats," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fu-Chao Zhang & Rui-Xia Weng & Di Li & Yong-Chang Li & Xiao-Xuan Dai & Shufen Hu & Qian Sun & Rui Li & Guang-Yin Xu, 2024. "A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Ren-Wen Han & Zi-Yi Zhang & Chen Jiao & Ze-Yu Hu & Bing-Xing Pan, 2024. "Synergism between two BLA-to-BNST pathways for appropriate expression of anxiety-like behaviors in male mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Lan Yan & Fengzhen Yang & Yajie Wang & Lingling Shi & Mei Wang & Diran Yang & Wenjing Wang & Yanbin Jia & Kwok-Fai So & Li Zhang, 2024. "Stress increases hepatic release of lipocalin 2 which contributes to anxiety-like behavior in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Robert N. Fetcho & Baila S. Hall & David J. Estrin & Alexander P. Walsh & Peter J. Schuette & Jesse Kaminsky & Ashna Singh & Jacob Roshgodal & Charlotte C. Bavley & Viraj Nadkarni & Susan Antigua & Th, 2023. "Regulation of social interaction in mice by a frontostriatal circuit modulated by established hierarchical relationships," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Jun Ma & John J. O’Malley & Malaz Kreiker & Yan Leng & Isbah Khan & Morgan Kindel & Mario A. Penzo, 2024. "Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Nicole Eichert & Jordan DeKraker & Amy F. D. Howard & Istvan N. Huszar & Silei Zhu & Jérôme Sallet & Karla L. Miller & Rogier B. Mars & Saad Jbabdi & Boris C. Bernhardt, 2024. "Hippocampal connectivity patterns echo macroscale cortical evolution in the primate brain," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Longyu Ma & Lupeng Yue & Shuting Liu & Shi Xu & Jifu Tong & Xiaoyan Sun & Li Su & Shuang Cui & Feng-Yu Liu & You Wan & Ming Yi, 2024. "A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Masayuki Kikkawa & Akiyoshi Shimura & Kazuki Nakajima & Chihiro Morishita & Mina Honyashiki & Yu Tamada & Shinji Higashi & Masahiko Ichiki & Takeshi Inoue & Jiro Masuya, 2023. "Mediating Effects of Trait Anxiety and State Anxiety on the Effects of Physical Activity on Depressive Symptoms," IJERPH, MDPI, vol. 20(7), pages 1-12, March.
    9. Reidun Aesoy & Haruna Muwonge & Kathrine S Asrud & Misbah Sabir & Solveig L Witsoe & Ronja Bjornstad & Reidun K Kopperud & Erling A Hoivik & Stein Ove Doskeland & Marit Bakke, 2018. "Deletion of exchange proteins directly activated by cAMP (Epac) causes defects in hippocampal signaling in female mice," PLOS ONE, Public Library of Science, vol. 13(7), pages 1-25, July.
    10. Kuikui Zhou & Hua Xu & Shanshan Lu & Shaolei Jiang & Guoqiang Hou & Xiaofei Deng & Miao He & Yingjie Zhu, 2022. "Reward and aversion processing by input-defined parallel nucleus accumbens circuits in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Bob Bramson & Sjoerd Meijer & Annelies Nuland & Ivan Toni & Karin Roelofs, 2023. "Anxious individuals shift emotion control from lateral frontal pole to dorsolateral prefrontal cortex," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    12. Huiling Yu & Liping Chen & Huiyang Lei & Guilin Pi & Rui Xiong & Tao Jiang & Dongqin Wu & Fei Sun & Yang Gao & Yuanhao Li & Wenju Peng & Bingyu Huang & Guoda Song & Xin Wang & Jingru Lv & Zetao Jin & , 2022. "Infralimbic medial prefrontal cortex signalling to calbindin 1 positive neurons in posterior basolateral amygdala suppresses anxiety- and depression-like behaviours," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Miao Li & Guang Yang, 2024. "A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Kelsey M. Vollmer & Lisa M. Green & Roger I. Grant & Kion T. Winston & Elizabeth M. Doncheck & Christopher W. Bowen & Jacqueline E. Paniccia & Rachel E. Clarke & Annika Tiller & Preston N. Siegler & B, 2022. "An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    15. Yanyu Zhou & Xiaoqi Lin & Yingfu Jiao & Dan Yang & Zhengyu Li & Ling Zhu & Yixuan Li & Suqing Yin & Quanfu Li & Saihong Xu & Dan Tang & Song Zhang & Weifeng Yu & Po Gao & Liqun Yang, 2024. "A brain-to-liver signal mediates the inhibition of liver regeneration under chronic stress in mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Nahoko Kuga & Ryota Nakayama & Shota Morikawa & Haruya Yagishita & Daichi Konno & Hiromi Shiozaki & Natsumi Honjoya & Yuji Ikegaya & Takuya Sasaki, 2023. "Hippocampal sharp wave ripples underlie stress susceptibility in male mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Carole Morel & Sarah E. Montgomery & Long Li & Romain Durand-de Cuttoli & Emily M. Teichman & Barbara Juarez & Nikos Tzavaras & Stacy M. Ku & Meghan E. Flanigan & Min Cai & Jessica J. Walsh & Scott J., 2022. "Midbrain projection to the basolateral amygdala encodes anxiety-like but not depression-like behaviors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    18. Liang Fang & Chanjuan Zhou & Shunjie Bai & Chenglong Huang & Junxi Pan & Ling Wang & Xinfa Wang & Qiang Mao & Lu Sun & Peng Xie, 2015. "The C825T Polymorphism of the G-Protein β3 Gene as a Risk Factor for Depression: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-11, July.
    19. Ya-Wei Ji & Zi-Lin Shen & Xue Zhang & Kairan Zhang & Tao Jia & Xiangying Xu & Huizhen Geng & Yu Han & Cui Yin & Jian-Jun Yang & Jun-Li Cao & Chunyi Zhou & Cheng Xiao, 2023. "Plasticity in ventral pallidal cholinergic neuron-derived circuits contributes to comorbid chronic pain-like and depression-like behaviour in male mice," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    20. James O Groves & Isla Leslie & Guo-Jen Huang & Stephen B McHugh & Amy Taylor & Richard Mott & Marcus Munafò & David M Bannerman & Jonathan Flint, 2013. "Ablating Adult Neurogenesis in the Rat Has No Effect on Spatial Processing: Evidence from a Novel Pharmacogenetic Model," PLOS Genetics, Public Library of Science, vol. 9(9), pages 1-16, September.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56258-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.