There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (5HT) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via 5HT2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust patterned respiratory recovery after a near lifetime of paralysis.

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Published in Nature Communications, v. 9, article no. 4843, p. 1-14.

© The Author(s) 2018

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Financial support was provided by The International Spinal Research Trust (STR117 to W.J.A., J.S. and P.M.W.), Craig H. Neilsen Foundation (221988 to W.J.A.), Wings for Life (WFL-US-027/14 to P.M.W.), the NIH (NS025713 to J.S.; R21OD018297 and R01NS101105 to W.J.A.), The Brumagin-Nelson Fund, the Hong Kong Spinal Cord Injury Fund, the Kaneko Family Fund and Unite 2 Fight Paralysis.

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Further information on research design is available in the Nature Research Reporting Summary linked to this article.

The data sets generated and/or analysed during the current study are available from the corresponding authors on reasonable request.

Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-018-06937-0.

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