V2a neurons restore diaphragm function in mice following spinal cord injury

Victoria N. Jensen, Emily E. Huffman, Frank L. Jalufka, Anna L. Pritchard, Sarah Baumgartner, Ian Walling, Holly C. Gibbs, Dylan A. McCreedy, Warren J. Alilain, Steven A. Crone

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The specific roles that different types of neurons play in recovery from injury is poorly understood. Here, we show that increasing the excitability of ipsilaterally projecting, excitatory V2a neurons using designer receptors exclusively activated by designer drugs (DREADDs) restores rhythmic bursting activity to a previously paralyzed diaphragm within hours, days, or weeks following a C2 hemisection injury. Further, decreasing the excitability of V2a neurons impairs tonic diaphragm activity after injury as well as activation of inspiratory activity by chemosensory stimulation, but does not impact breathing at rest in healthy animals. By examining the patterns of muscle activity produced by modulating the excitability of V2a neurons, we provide evidence that V2a neurons supply tonic drive to phrenic circuits rather than increase rhythmic inspiratory drive at the level of the brainstem. Our results demonstrate that the V2a class of neurons contribute to recovery of respiratory function following injury. We propose that altering V2a excitability is a potential strategy to prevent respiratory motor failure and promote recovery of breathing following spinal cord injury.

Original languageEnglish
Article numbere2313594121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number11
DOIs
StatePublished - Mar 12 2024

Bibliographical note

Publisher Copyright:
© 2024 National Academy of Sciences. All rights reserved.

Funding

We would like to thank Daimen R. S. Britsch and Lydia E. Strattan for developing the technique to record electromyography from the mouse diaphragm. Some of the material in this manuscript was used in the doctoral dissertation of Victoria Jensen. This publication was supported by a collaborative grant to S.A.C. and W.J.A. from the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through Grant UL1TR001998, the University of Kentucky College of Medicine, and Office of the Vice President for Research as well as by the CCTST at the University of Cincinnati-funded by the NIH Clinical and Translational Science Award (CTSA) program, Grant 5UL1TR001425-03. The CTSA program is led by the NIH\u2019s National Center for Advancing Translational Sciences (NCATS). Additional support was provided by Craig H. Neilsen Foundation Grants #598928 (S.A.C.) and #598741 (W.J.A.), Cincinnati Children\u2019s Hospital Medical Center Research and Innovation Pilot Grant (S.A.C.), the L.B. Research and Education Foundation (I.W.), Mission Connect- a program of TIRR Foundation (D.A.M.), Silicon Valley Community Foundation CZI Imaging Scientist Program 2019-198168 (H.C.G.) as well as the NIH R01NS112255 (S.A.C.), R01NS101105 (W.J.A.), and R01NS122961 (D.A.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. ACKNOWLEDGMENTS. We would like to thank Daimen R. S. Britsch and Lydia E. Strattan for developing the technique to record electromyography from the mouse diaphragm. Some of the material in this manuscript was used in the doctoral dissertation of Victoria Jensen.This publication was supported by a collaborative grant to S.A.C. and W.J.A. from the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, through Grant UL1TR001998, the University of Kentucky College of Medicine, and Office of the Vice President for Research as well as by the CCTST at the University of Cincinnati-funded by the NIH Clinical and Translational Science Award (CTSA) program, Grant 5UL1TR001425-03.The CTSAprogram is led by the NIH\u2019s National Center for Advancing Translational Sciences (NCATS). Additional support was provided by Craig H. Neilsen Foundation Grants #598928 (S.A.C.) and #598741 (W.J.A.), Cincinnati Children\u2019s Hospital Medical Center Research and Innovation Pilot Grant (S.A.C.), the L.B. Research and Education Foundation (I.W.), Mission Connect-a program of TIRR Foundation (D.A.M.), Silicon Valley Community Foundation CZI Imaging Scientist Program 2019-198168 (H.C.G.) as well as the NIH R01NS112255 (S.A.C.), R01NS101105 (W.J.A.), and R01NS122961 (D.A.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.

FundersFunder number
Mission Connect
University of Kentucky College of Medicine
NATA Research and Education Foundation
Office of the Executive Vice President for Research and Partnerships, Purdue University
TIRR Foundation
National Center for Research Resources
Cincinnati Children's Hospital Medical Center
National Center for Advancing Translational Sciences (NCATS)
National Institutes of Health (NIH)UL1TR001998
National Institutes of Health (NIH)
Silicon Valley Community FoundationR01NS112255, R01NS101105, R01NS122961
Silicon Valley Community Foundation
Craig H. Neilsen Foundation598928, 598741
Craig H. Neilsen Foundation
CCTST5UL1TR001425-03

    Keywords

    • V2a neuron
    • breathing
    • electromyography
    • neuroplasticity
    • spinal cord injury

    ASJC Scopus subject areas

    • General

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