Skip to main content
SpringerLink
Log in

Three-phase Enriched Environment Improves Post-stroke Gait Dysfunction via Facilitating Neuronal Plasticity in the Bilateral Sensorimotor Cortex: A Multimodal MRI/PET Analysis in Rats

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

The three-phase Enriched Environment (EE) paradigm has been shown to promote post-stroke functional improvement, but the neuronal mechanisms are still unclear. In this study, we applied a multimodal neuroimaging protocol combining magnetic resonance imaging (MRI) and positron emission tomography (PET) to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor cortex. Rats were subjected to permanent middle cerebral artery occlusion. The motor function of the rats was examined using the DigiGait test. MRI was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex. [18F]-fluorodeoxyglucose PET was used to detect glucose metabolism. Blood oxygen level-dependent (BOLD)-functional MRI (fMRI) was used to identify the regional brain activity and functional connectivity (FC). In addition, the expression of neuroplasticity-related signaling pathways including neurotrophic factors (BDNF/CREB), axonal guidance proteins (Robo1/Slit2), and axonal growth-inhibitory proteins (NogoA/NgR) as well as downstream proteins (RhoA/ROCK) in the bilateral sensorimotor cortex were measured by Western blots. Our results showed the three-phase EE improved the walking ability. Structural T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor cortex. PET-MRI fused images showed improved glucose metabolism in the corresponding regions after EE intervention. Specifically, the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory cortex. In addition, FC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE intervention. In addition, a strong correlation was found between increased functional connectivity and improved motor performance of limbs. Specifically, EE regulated the expression of neuroplasticity-related signaling, involving BDNF/CREB, Slit2/Robo1, as well as the axonal growth–inhibitory pathways Nogo-A/Nogo receptor and RhoA/ROCK in the bilateral sensorimotor cortex. Our results indicated that the three-phase enriched environment paradigm enhances neuronal plasticity of the bilateral sensorimotor cortex and consequently ameliorates post-stroke gait deficits. These findings might provide some new clues for the development of EE and thus facilitate the clinical translation of EE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Hyndman D, Ashburn A, Stack E. Fall events among people with stroke living in the community: Circumstances of falls and characteristics of fallers. Arch Phys Med Rehabil 2002, 83: 165–170.

    Article  PubMed  Google Scholar 

  2. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet 2011, 377: 1693–1702.

    Article  PubMed  Google Scholar 

  3. Schmid AA, Van Puymbroeck M, Altenburger PA, Miller KK, Combs SA, Page SJ. Balance is associated with quality of life in chronic stroke. Top Stroke Rehabil 2013, 20: 340–346.

    Article  PubMed  Google Scholar 

  4. Mao R, Zong N, Hu Y, Chen Y, Xu Y. Neuronal death mechanisms and therapeutic strategy in ischemic stroke. Neurosci Bull 2022, 38: 1229–1247.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wang H, Arceo R, Chen S, Ding L, Jia J, Yao J. Effectiveness of interventions to improve hand motor function in individuals with moderate to severe stroke: a systematic review protocol. BMJ Open 2019, 9: e032413.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lee KB, Lim SH, Kim KH, Kim KJ, Kim YR, Chang WN. Six-month functional recovery of stroke patients: a multi-time-point study. Int J Rehabil Res 2015, 38: 173–180.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Johansson B, Ohlsson A. Environment, social interaction, and physical activity as determinants of functional outcome after cerebral infarction in the rat. Exp Neurol 1996, 139: 322–327.

    Article  CAS  PubMed  Google Scholar 

  8. Nygren J, Wieloch T. Enriched environment enhances recovery of motor function after focal ischemia in mice, and downregulates the transcription factor NGFI-A. J Cereb Blood Flow Metab 2005, 25: 1625–1633.

    Article  CAS  PubMed  Google Scholar 

  9. Zhan Y, Li MZ, Yang L, Feng XF, Lei JF, Zhang N, et al. The three-phase enriched environment paradigm promotes neurovascular restorative and prevents learning impairment after ischemic stroke in rats. Neurobiol Dis 2020, 146: 105091.

    Article  CAS  PubMed  Google Scholar 

  10. Annweiler C, Beauchet O, Bartha R, Wells JL, Borrie MJ, Hachinski V, et al. Motor cortex and gait in mild cognitive impairment: A magnetic resonance spectroscopy and volumetric imaging study. Brain 2013, 136: 859–871.

    Article  PubMed  Google Scholar 

  11. Zingg B, Hintiryan H, Gou L, Song MY, Bay M, Bienkowski MS, et al. Neural networks of the mouse neocortex. Cell 2014, 156: 1096–1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sherman SM. Thalamus plays a central role in ongoing cortical functioning. Nat Neurosci 2016, 19: 533–541.

    Article  CAS  PubMed  Google Scholar 

  13. Takakusaki K. Neurophysiology of gait: From the spinal cord to the frontal lobe. Mov Disord 2013, 28: 1483–1491.

    Article  PubMed  Google Scholar 

  14. van Meer MPA, Otte WM, van der Marel K, Nijboer CH, Kavelaars A, van der Sprenkel JWB, et al. Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity. J Neurosci 2012, 32: 4495–4507.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lindau NT, Bänninger BJ, Gullo M, Good NA, Bachmann LC, Starkey ML, et al. Rewiring of the corticospinal tract in the adult rat after unilateral stroke and anti-Nogo-a therapy. Brain 2014, 137: 739–756.

    Article  PubMed  Google Scholar 

  16. Wang H, Xiong X, Zhang K, Wang X, Sun C, Zhu B, et al. Motor network reorganization after motor imagery training in stroke patients with moderate to severe upper limb impairment. CNS Neurosci Ther 2023, 29: 619–632.

    Article  PubMed  Google Scholar 

  17. Yu K, Wu Y, Zhang Q, Xie H, Liu G, Guo Z, et al. Enriched environment induces angiogenesis and improves neural function outcomes in rat stroke model. J Neurol Sci 2014, 347: 275–280.

    Article  PubMed  Google Scholar 

  18. Zhang X, Chen XP, Lin JB, Xiong Y, Liao WJ, Wan Q. Effect of enriched environment on angiogenesis and neurological functions in rats with focal cerebral ischemia. Brain Res 2017, 1655: 176–185.

    Article  CAS  PubMed  Google Scholar 

  19. Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 2001, 21: 5272–5280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012, 64: 238–258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Alpár A, Tortoriello G, Calvigioni D, Niphakis MJ, Milenkovic I, Bakker J, et al. Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 2014, 5: 4421.

    Article  PubMed  Google Scholar 

  22. Mu JD, Ma LX, Zhang Z, Qian X, Zhang QY, Ma LH, et al. The factors affecting neurogenesis after stroke and the role of acupuncture. Front Neurol 2023, 14: 1082625.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Rejdak K, Sienkiewicz-Jarosz H, Bienkowski P, Alvarez A. Modulation of neurotrophic factors in the treatment of dementia, stroke and TBI: Effects of Cerebrolysin. Med Res Rev 2023, 43: 1668–1700.

    Article  CAS  PubMed  Google Scholar 

  24. Nishiyama M, von Schimmelmann MJ, Togashi K, Findley WM, Hong K. Membrane potential shifts caused by diffusible guidance signals direct growth-cone turning. Nat Neurosci 2008, 11: 762–771.

    Article  CAS  PubMed  Google Scholar 

  25. Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 2011, 10: 209–219.

    Article  CAS  PubMed  Google Scholar 

  26. Whitford KL, Marillat V, Stein E, Goodman CS, Tessier-Lavigne M, Chédotal A, et al. Regulation of cortical dendrite development by Slit-Robo interactions. Neuron 2002, 33: 47–61.

    Article  CAS  PubMed  Google Scholar 

  27. Andres RH, Horie N, Slikker W, Keren-Gill H, Zhan K, Sun G, et al. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 2011, 134: 1777–1789.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Schwab ME. Nogo and axon regeneration. Curr Opin Neurobiol 2004, 14: 118–124.

    Article  CAS  PubMed  Google Scholar 

  29. Schwab ME, Strittmatter SM. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol 2014, 27: 53–60.

    Article  CAS  PubMed  Google Scholar 

  30. Yang L, Li M, Zhan Y, Feng X, Lu Y, Li M, et al. The impact of ischemic stroke on gray and white matter injury correlated with motor and cognitive impairments in permanent MCAO rats: a multimodal MRI-based study. Front Neurol 2022, 13: 834329.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li M, Zhao Y, Zhan Y, Yang L, Feng X, Lu Y, et al. Enhanced white matter reorganization and activated brain glucose metabolism by enriched environment following ischemic stroke: micro PET/CT and MRI study. Neuropharmacology 2020, 176: 108202.

    Article  CAS  PubMed  Google Scholar 

  32. Nie B, Chen K, Zhao S, Liu J, Gu X, Yao Q, et al. A rat brain MRI template with digital stereotaxic atlas of fine anatomical delineations in paxinos space and its automated application in voxel-wise analysis. Hum Brain Mapp 2013, 34: 1306–1318.

    Article  PubMed  Google Scholar 

  33. Dolui S, Li Z, Nasrallah IM, Detre JA, Wolk DA. Arterial spin labeling versus 18F-FDG-PET to identify mild cognitive impairment. Neuroimage Clin 2020, 25: 102146.

    Article  PubMed  Google Scholar 

  34. Liu P, Tu H, Zhang A, Yang C, Liu Z, Lei L, et al. Brain functional alterations in MDD patients with somatic symptoms: A resting-state fMRI study. J Affect Disord 2021, 295: 788–796.

    Article  PubMed  Google Scholar 

  35. Mandeville ET, Ayata C, Zheng Y, Mandeville JB. Translational MR neuroimaging of stroke and recovery. Transl Stroke Res 2017, 8: 22–32.

    Article  CAS  PubMed  Google Scholar 

  36. Kimura-Ohba S, Yang Y, Thompson J, Kimura T, Salayandia VM, Cosse M, et al. Transient increase of fractional anisotropy in reversible vasogenic edema. J Cereb Blood Flow Metab 2016, 36: 1731–1743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fellgiebel A, Wille P, Müller MJ, Winterer G, Scheurich A, Vucurevic G, et al. Ultrastructural hippocampal and white matter alterations in mild cognitive impairment: A diffusion tensor imaging study. Dement Geriatr Cogn Disord 2004, 18: 101–108.

    Article  PubMed  Google Scholar 

  38. Magistretti PJ, Allaman I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 2015, 86: 883–901.

    Article  CAS  PubMed  Google Scholar 

  39. Joy MT, Carmichael ST. Encouraging an excitable brain state: Mechanisms of brain repair in stroke. Nat Rev Neurosci 2021, 22: 38–53.

    Article  CAS  PubMed  Google Scholar 

  40. Harris JA, Mihalas S, Hirokawa KE, Whitesell JD, Choi H, Bernard A, et al. Hierarchical organization of cortical and thalamic connectivity. Nature 2019, 575: 195–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Usrey WM, Sherman SM. Corticofugal circuits: Communication lines from the cortex to the rest of the brain. J Comp Neurol 2019, 527: 640–650.

    Article  PubMed  Google Scholar 

  42. Tennant KA, Taylor SL, White ER, Brown CE. Optogenetic rewiring of thalamocortical circuits to restore function in the stroke injured brain. Nat Commun 2017, 8: 15879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Faverjon S, Silveira DC, Fu DD, Cha BH, Akman C, Hu Y, et al. Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology 2002, 59: 1356–1364.

    Article  CAS  PubMed  Google Scholar 

  44. Kondo M, Takei Y, Hirokawa N. Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment. Neuron 2012, 73: 743–757.

    Article  CAS  PubMed  Google Scholar 

  45. Wang L, Cao M, Pu T, Huang H, Marshall C, Xiao M. Enriched physical environment attenuates spatial and social memory impairments of aged socially isolated mice. Int J Neuropsychopharmacol 2018, 21: 1114–1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (82174471).

Author information

Authors and Affiliations

  1. School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China

    Yun Lu, Ziyue Lin, Mingcong Li, Yuming Zhuang & Hui Zhao

  2. Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, 100069, China

    Yun Lu, Ziyue Lin, Mingcong Li, Yuming Zhuang & Hui Zhao

  3. Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China

    Binbin Nie

  4. Medical Imaging Laboratory of Core Facility Center, Capital Medical University, Beijing, 100069, China

    Jianfeng Lei & Yuanyuan Zhao

Authors
  1. Yun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziyue Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mingcong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuming Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Binbin Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jianfeng Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanyuan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hui Zhao.

Ethics declarations

Conflict of interest

The authors declare no competing financial interests.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 161 kb)

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

Lu, Y., Lin, Z., Li, M. et al. Three-phase Enriched Environment Improves Post-stroke Gait Dysfunction via Facilitating Neuronal Plasticity in the Bilateral Sensorimotor Cortex: A Multimodal MRI/PET Analysis in Rats. Neurosci. Bull. (2023). https://doi.org/10.1007/s12264-023-01155-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12264-023-01155-1

Keywords

Search

Navigation