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.

  • Immediate Communication
  • Published:

Physical exercise rescues cocaine-evoked synaptic deficits in motor cortex

Molecular Psychiatry volume 26, pages 6187–6197 (2021)Cite this article

Subjects

Abstract

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.

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: Physical exercise relieves cocaine-induced motor-learning deficits and spine deficits.
Fig. 2: Physical exercise restored normal synaptic transmissions in motor cortex.
Fig. 3: Modulation of inhibitory neuron activity by exercise training.
Fig. 4: Exercise activates mTOR-S6 pathway in motor cortex of cocaine-exposed mice.
Fig. 5: Exercise potentiates apical spines via facilitating de novo protein synthesis.

Similar content being viewed by others

References

  1. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci. 2005;8:1481–9.

    Article  CAS  PubMed  Google Scholar 

  2. Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2011;12:652–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kosten TR, Scanley BE, Tucker KA, Oliveto A, Prince C, Sinha R, et al. Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology. 2006;31:644–50.

    Article  CAS  PubMed  Google Scholar 

  4. Smolka MN, Bühler M, Klein S, Zimmermann U, Mann K, Heinz A, et al. Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery. Psychopharmacology. 2006;184:577–88.

    Article  CAS  PubMed  Google Scholar 

  5. Peng SY, Shi Z, Zhou DS, Wang XY, Li XX, Liu XL, et al. Reduced motor cortex GABA(B)R function following chronic alcohol exposure. Mol Psychiatry. 2021;26:383–95.

    Article  CAS  PubMed  Google Scholar 

  6. Huang X, Chen YY, Shen Y, Cao X, Li A, Liu Q, et al. Methamphetamine abuse impairs motor cortical plasticity and function. Mol Psychiatry. 2017;22:1274–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shen Y, Cao X, Shan C, Dai W, Yuan TF. Heroin addiction impairs human cortical plasticity. Biol Psychiatry. 2017;81:e49–e50.

    Article  PubMed  Google Scholar 

  8. Martin-Rodriguez JF, Ruiz-Veguilla M, Alvarez de Toledo P, Aizpurua-Olaizola O, Zarandona I, Canal-Rivero M, et al. Impaired motor cortical plasticity associated with cannabis use disorder in young adults. Addiction Biol. 2021;26:e12912.

    Article  CAS  Google Scholar 

  9. Chen K, Zhang L, Tan M, Lai CS, Li A, Ren C, et al. Treadmill exercise suppressed stress-induced dendritic spine elimination in mouse barrel cortex and improved working memory via BDNF/TrkB pathway. Transl Psychiatry. 2017;7:e1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen K, Zheng Y, Wei JA, Ouyang H, Huang X, Zhang F, et al. Exercise training improves motor skill learning via selective activation of mTOR. Sci Adv. 2019;5:eaaw1888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang G, Pan F, Gan WB. Stably maintained dendritic spines are associated with lifelong memories. Nature. 2009;462:920–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang G, Lai CS, Cichon J, Ma L, Li W, Gan WB. Sleep promotes branch-specific formation of dendritic spines after learning. Science. 2014;344:1173–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cichon J, Gan WB. Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity. Nature. 2015;520:180–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Adler A, Zhao R, Shin ME, Yasuda R, Gan WB. Somatostatin-expressing interneurons enable and maintain learning-dependent sequential activation of pyramidal neurons. Neuron. 2019;102:202–16. e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sutton MA, Schuman EM. Dendritic protein synthesis, synaptic plasticity, and memory. Cell. 2006;127:49–58.

    Article  CAS  PubMed  Google Scholar 

  16. Luft AR, Buitrago MM, Ringer T, Dichgans J, Schulz JB. Motor skill learning depends on protein synthesis in motor cortex after training. J Neurosci. 2004;24:6515–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 2007;13:252–9.

    Article  CAS  PubMed  Google Scholar 

  18. Ruvinsky I, Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci. 2006;31:342–8.

    Article  CAS  PubMed  Google Scholar 

  19. Tewari S, Greenberg SA, Do K, Grey PA. The response of rat brain protein synthesis to ethanol and sodium barbital. Alcohol Drug Res. 1987;7:243–58.

    CAS  PubMed  Google Scholar 

  20. Chen K, Yang G, So KF, Zhang L. Activation of cortical somatostatin interneurons rescues synapse loss and motor deficits after acute MPTP infusion. iScience. 2019;17:230–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bai Y, Li M, Zhou Y, Ma L, Qiao Q, Hu W, et al. Abnormal dendritic calcium activity and synaptic depotentiation occur early in a mouse model of Alzheimer’s disease. Mol Neurodegeneration. 2017;12:86.

    Article  Google Scholar 

  22. Manns ID, Sakmann B, Brecht M. Sub- and suprathreshold receptive field properties of pyramidal neurones in layers 5A and 5B of rat somatosensory barrel cortex. J Physiol. 2004;556:601–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Urban-Ciecko J, Barth AL. Somatostatin-expressing neurons in cortical networks. Nat Rev Neurosci. 2016;17:401–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alvaro-Bartolome M, Garcia-Sevilla JA. Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents. Neuroscience. 2013;247:294–308.

    Article  CAS  PubMed  Google Scholar 

  25. Li Y, Corradetti MN, Inoki K, Guan KL. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem. Sci. 2004;29:32–8.

    Article  PubMed  Google Scholar 

  26. Puighermanal E, Marsicano G, Busquets-Garcia A, Lutz B, Maldonado R, Ozaita A. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat Neurosci. 2009;12:1152–8.

    Article  CAS  PubMed  Google Scholar 

  27. Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61:10–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Edwards DR, Mahadevan LC. Protein synthesis inhibitors differentially superinduce c-fos and c-jun by three distinct mechanisms: lack of evidence for labile repressors. EMBO J. 1992;11:2415–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis. Neurosci Biobehav Rev. 2013;37:1622–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sanchez V, Bakhti-Suroosh A, Chen A, Brunzell DH, Erisir A, Lynch WJ. Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine-seeking following extended access self-administration. Eur J Neurosci. 2019;50:2707–21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. O’Dell SJ, Galvez BA, Ball AJ, Marshall JF. Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals. Synapse. 2012;66:71–80.

    Article  PubMed  Google Scholar 

  32. Kawai R, Markman T, Poddar R, Ko R, Fantana AL, Dhawale AK, et al. Motor cortex is required for learning but not for executing a motor skill. Neuron. 2015;86:800–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002;159:1642–52.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Younts TJ, Monday HR, Dudok B, Klein ME, Jordan BA, Katona I, et al. Presynaptic protein synthesis is required for long-term plasticity of GABA release. Neuron. 2016;92:479–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Steward O, Schuman EM. Protein synthesis at synaptic sites on dendrites. Annu. Rev. Neurosci. 2001;24:299–325.

    Article  CAS  PubMed  Google Scholar 

  36. Salery M, Dos Santos M, Saint-Jour E, Moumné L, Pagès C, Kappès V, et al. Activity-regulated cytoskeleton-associated protein accumulates in the nucleus in response to cocaine and acts as a brake on chromatin remodeling and long-term behavioral alterations. Biol Psychiatry. 2017;81:573–84.

    Article  CAS  PubMed  Google Scholar 

  37. Nadel J, Huang T, Xia Z, Burlin T, Zametkin A, Smith CB. Voluntary exercise regionally augments rates of cerebral protein synthesis. Brain Res. 2013;1537:125–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ying Z, Roy RR, Edgerton VR, Gómez-Pinilla F. Exercise restores levels of neurotrophins and synaptic plasticity following spinal cord injury. Exp Neurol. 2005;193:411–9.

    Article  CAS  PubMed  Google Scholar 

  39. Vaynman S, Ying Z, Gomez-Pinilla F. Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity. Neuroscience 2003;122:647–57.

    Article  CAS  PubMed  Google Scholar 

  40. Kim J, Guan KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 2019;21:63–71.

    Article  CAS  PubMed  Google Scholar 

  41. Watson K, Baar K. mTOR and the health benefits of exercise. Semin Cell Dev Biol. 2014;36:130–9.

    Article  CAS  PubMed  Google Scholar 

  42. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30:464–72.

    Article  CAS  PubMed  Google Scholar 

  43. Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab. 2014;25:89–98.

    Article  CAS  PubMed  Google Scholar 

  44. Brynildsen JK, Lee BG, Perron IJ, Jin S, Kim SF, Blendy JA. Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal. Proc Natl Acad Sci USA. 2018;115:4282–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Chaoran Ren for technical supports in this work.

Author contributions

LZ, TC, and TFY conceived all experiments. TC performed all molecular, behavioral assays and two-photon calcium imaging. XDH performed the electrophysiological studies. XFH, SQW, and TC executed the two-photon spine imaging. JW and KC helped in the in vivo imaging studies. LY assisted in the molecular and behavioral assays. LZ analyzed all experimental data. LZ, TFY, and KFS supervised all experiments. The manuscript was prepared by LZ, TC, and TFY with inputs from all authors.

Funding

This study was funded by National Natural Science Foundation of China (32070955 to LZ, 31771215, 81822017 to TFY), National Key Research and Development Program of China (2020YFA0113600) to TFY and LZ, Science and Technology Program of Guangdong (2018B030334001) to KFS, Outstanding Scholar Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110102002) to KFS and LZ, Guangdong Natural Science Foundation (2019A1515011772) to LZ, and Science and Technology Program of Guangzhou, China (202007030012) to KFS and LZ.

Author information

Authors and Affiliations

  1. Key Laboratory of Central CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

    Tong Cheng, Xiao-Dan Huang, Xue-Fei Hu, Kai Chen, Ji-An Wei, Lan Yan, Kwok-Fai So & Li Zhang

  2. Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xue-Fei Hu

  3. College of Life Science and Technology, Jinan University, Guangzhou, China

    Si-Qi Wang

  4. State Key Laboratory of Brain and Cognitive Science, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

    Kwok-Fai So

  5. Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, China

    Kwok-Fai So & Li Zhang

  6. Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China

    Kwok-Fai So & Li Zhang

  7. Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao, China

    Kwok-Fai So & Li Zhang

  8. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Ti-Fei Yuan

  9. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

    Ti-Fei Yuan

  10. Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, China

    Ti-Fei Yuan

Authors
  1. Tong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Dan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue-Fei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Si-Qi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ji-An Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kwok-Fai So
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ti-Fei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ti-Fei Yuan or Li Zhang.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, T., Huang, XD., Hu, XF. et al. Physical exercise rescues cocaine-evoked synaptic deficits in motor cortex. Mol Psychiatry 26, 6187–6197 (2021). https://doi.org/10.1038/s41380-021-01336-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01336-2

This article is cited by

Search

Advanced search

Quick links