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Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke

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Abstract

Ischemic stroke often leads to permanent neurological impairments, largely due to limited neuroplasticity in adult central nervous system. Here, we first showed that the expression of Sonic Hedgehog (Shh) in corticospinal neurons (CSNs) peaked at the 2nd postnatal week, when corticospinal synaptogenesis occurs. Overexpression of Shh in adult CSNs did not affect motor functions and had borderline effects on promoting the recovery of skilled locomotion following ischemic stroke. In contrast, CSNs-specific Shh overexpression significantly enhanced the efficacy of rehabilitative training, resulting in robust axonal sprouting and synaptogenesis of corticospinal axons into the denervated spinal cord, along with significantly improved behavioral outcomes. Mechanistically, combinatory treatment led to additional mTOR activation in CSNs when compared to that evoked by rehabilitative training alone. Taken together, our study unveiled a role of Shh, a morphogen involved in early development, in enhancing neuroplasticity, which significantly improved the outcomes of rehabilitative training. These results thus provide novel insights into the design of combinatory treatment for stroke and traumatic central nervous system injuries.

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Data Availability

All original data will be made available on reasonable request to Shukun Hu.

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Funding

This work was supported by grants from National Natural Science Foundation (81501007), the Tibet Natural Science Foundation (XZ2019ZR-ZY41), and Research Initiation Fund of Huashan Hospital Affiliated to Fudan University (2021QD044).

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Authors and Affiliations

  1. Department of Neurosurgery and Neurocritical Care, Affiliated Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, Shanghai, 200042, China

    Biwu Wu, Lei Yang, Caihua **, Haijun Yao, Long Chen, Gang Wu, Zhouying Du, ** Hu & Shukun Hu

  2. National Center for Neurological Disorders, Shanghai, China

    Biwu Wu, Lei Yang, Caihua **, Haijun Yao, Long Chen, Gang Wu, Zhouying Du, ** Hu & Shukun Hu

  3. Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China

    Biwu Wu, Lei Yang, Caihua **, Haijun Yao, Long Chen, Gang Wu, Zhouying Du, ** Hu & Shukun Hu

  4. Neurosurgical Institute of Fudan University, Shanghai, China

    Biwu Wu, Lei Yang, Caihua **, Haijun Yao, Long Chen, Gang Wu, Zhouying Du, ** Hu & Shukun Hu

  5. Shanghai Clinical Medical Center of Neurosurgery, Shanghai, China

    Biwu Wu, Lei Yang, Caihua **, Haijun Yao, Long Chen, Gang Wu, Zhouying Du, ** Hu & Shukun Hu

  6. Pain Department of Yueyang Integrated Traditional Chinese and Western Medicine Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Fengqi Fan

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Contributions

B.W. and S.H. conceived the experiments. B.W., L.Y., C.X., F.F., H.Y., L.C., G.W., Z.D., and J.H. performed the experiments. B.W. and S.H. prepared the manuscript with input from all authors.

Corresponding author

Correspondence to Shukun Hu.

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Ethics Approval

All surgical procedures and behavioral measurements involved in this study were approved by the Use and Care of Animals Committee of Fudan University. All experiments were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals guidelines.

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Wu, B., Yang, L., **, C. et al. Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke. Mol Neurobiol 61, 2186–2196 (2024). https://doi.org/10.1007/s12035-023-03642-y

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