Development and characterization of a chronic implant mouse model for vagus nerve stimulation

  1. Ibrahim T Mughrabi
  2. Jordan Hickman
  3. Naveen Jayaprakash
  4. Dane Thompson
  5. Umair Ahmed
  6. Eleni S Papadoyannis
  7. Yao-Chuan Chang
  8. Adam Abbas
  9. Timir Datta-Chaudhuri
  10. Eric H Chang
  11. Theodoros P Zanos
  12. Sunhee C Lee
  13. Robert C Froemke
  14. Kevin J Tracey
  15. Cristin Welle  Is a corresponding author
  16. Yousef Al-Abed
  17. Stavros Zanos  Is a corresponding author
  1. The Feinstein Institutes for Medical Research, United States
  2. University of Colorado Anschutz Medical Campus, United States
  3. New York University School of Medicine, United States

Abstract

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in 4 research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, and 4.

Article and author information

Author details

  1. Ibrahim T Mughrabi

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8057-6146
  2. Jordan Hickman

    Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
    Competing interests
    No competing interests declared.
  3. Naveen Jayaprakash

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  4. Dane Thompson

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  5. Umair Ahmed

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  6. Eleni S Papadoyannis

    Neuroscience, New York University School of Medicine, Manhattan, United States
    Competing interests
    No competing interests declared.
  7. Yao-Chuan Chang

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0340-4652
  8. Adam Abbas

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  9. Timir Datta-Chaudhuri

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  10. Eric H Chang

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  11. Theodoros P Zanos

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  12. Sunhee C Lee

    Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  13. Robert C Froemke

    New York University School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1230-6811
  14. Kevin J Tracey

    Labolatory of Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    Kevin J Tracey, K.J.T. holds patents broadly related to this work. He has assigned all rights to the Feinstein Institutes for Medical Research..
  15. Cristin Welle

    Neurosurgery and Physiology & Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
    For correspondence
    cristin.welle@cuanschutz.edu
    Competing interests
    No competing interests declared.
  16. Yousef Al-Abed

    Center for Molecular Innovation, The Feinstein Institutes for Medical Research, Manhasset, United States
    Competing interests
    No competing interests declared.
  17. Stavros Zanos

    Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, United States
    For correspondence
    szanos@northwell.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3967-8164

Funding

Defense Advanced Research Projects Agency (HR0011-17-2-0025)

  • Stavros Zanos

United Therapeutics Corporation

  • Stavros Zanos

Boston Scientific Corporation

  • Yousef Al-Abed

Defense Advanced Research Projects Agency (HR0011-17-2-0051)

  • Cristin Welle

Defense Advanced Research Projects Agency (N66001-17-2-4010)

  • Robert C Froemke

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD088411)

  • Robert C Froemke

Brain Research through Advancing Innovative Neurotechnologies (NS107616)

  • Robert C Froemke

National Institute on Deafness and Other Communication Disorders (DC12557)

  • Robert C Froemke

Howard Hughes Medical Institute (Faculty Scholarship)

  • Robert C Froemke

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments complied with relevant ethical guidelines and were approved by the Institutional Animal Care and Use Committee (IACUC) of the Feinstein Institutes for Medical Research (protocol numbers: 2016-029, 2017-010, and 2019-010) and University of Colorado Anschutz Medical Campus (protocol number: 00238).

Reviewing Editor

  1. Isaac M Chiu, Harvard Medical School, United States

Publication history

  1. Received: July 20, 2020
  2. Accepted: April 2, 2021
  3. Accepted Manuscript published: April 6, 2021 (version 1)
  4. Version of Record published: April 16, 2021 (version 2)

Copyright

© 2021, Mughrabi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ibrahim T Mughrabi
  2. Jordan Hickman
  3. Naveen Jayaprakash
  4. Dane Thompson
  5. Umair Ahmed
  6. Eleni S Papadoyannis
  7. Yao-Chuan Chang
  8. Adam Abbas
  9. Timir Datta-Chaudhuri
  10. Eric H Chang
  11. Theodoros P Zanos
  12. Sunhee C Lee
  13. Robert C Froemke
  14. Kevin J Tracey
  15. Cristin Welle
  16. Yousef Al-Abed
  17. Stavros Zanos
(2021)
Development and characterization of a chronic implant mouse model for vagus nerve stimulation
eLife 10:e61270.
https://doi.org/10.7554/eLife.61270

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