Abstract

There is clear evidence that the sympathetic nervous system (SNS) mediates bone metabolism. Histological studies show abundant SNS innervation of the periosteum and bone marrow-these nerves consist of noradrenergic fibers that immunostain for tyrosine hydroxylase, dopamine beta hydroxylase, or neuropeptide Y. Nonetheless, the brain sites that send efferent SNS outflow to bone have not yet been characterized. Using pseudorabies (PRV) viral transneuronal tracing, we report, for the first time, the identification of central SNS outflow sites that innervate bone. We find that the central SNS outflow to bone originates from 87 brain nuclei, sub-nuclei and regions of six brain divisions, namely the midbrain and pons, hypothalamus, hindbrain medulla, forebrain, cerebral cortex, and thalamus. We also find that certain sites, such as the raphe magnus (RMg) of the medulla and periaqueductal gray (PAG) of the midbrain, display greater degrees of PRV152 infection, suggesting that there is considerable site-specific variation in the levels of central SNS outflow to bone. This comprehensive compendium illustrating the central coding and control of SNS efferent signals to bone should allow for a greater understanding of the neural regulation of bone metabolism, and importantly and of clinical relevance, mechanisms for central bone pain.

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Author details

  1. Vitaly Ryu

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    vitaly.ryu@mssm.edu
    Competing interests
    Vitaly Ryu, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8068-4577
  2. Anisa Azatovna Gumerova

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  3. Ronit Witztum

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  4. Funda Korkmaz

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  5. Liam Cullen

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  6. Hasni Kannangara

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  7. Ofer Moldavski

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  8. Orly Barak

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  9. Daria Lizneva

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Daria Lizneva, Reviewing editor, eLife.
  10. Ki A Goosens

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Ki A Goosens, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5246-2261
  11. Sarah Stanley

    Department of Medicine and of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  12. Se-Min Kim

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Se-Min Kim, Reviewing editor, eLife.
  13. Tony Yuen

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Tony Yuen, Senior editor, eLife.
  14. Mone Zaidi

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    mone.zaidi@mountsinai.org
    Competing interests
    Mone Zaidi, consults for Gershon Lehmann, Guidepoint and Coleman groups..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5911-9522

Funding

National Institute on Aging (R01 AG071870)

  • Se-Min Kim
  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (U01 AG073148)

  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (R01 AG074092)

  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (U19 AG060917)

  • Mone Zaidi

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK107670)

  • Tony Yuen
  • Mone Zaidi

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 procedures were approved by the Mount Sinai Institutional Animal Care and Use Committee and were performed in accordance with Public Health Service and United States Department of Agriculture guidelines (IBC: SPROTO202200000224; IACUC: PROTO202100074).

Copyright

© 2024, Ryu 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. Vitaly Ryu
  2. Anisa Azatovna Gumerova
  3. Ronit Witztum
  4. Funda Korkmaz
  5. Liam Cullen
  6. Hasni Kannangara
  7. Ofer Moldavski
  8. Orly Barak
  9. Daria Lizneva
  10. Ki A Goosens
  11. Sarah Stanley
  12. Se-Min Kim
  13. Tony Yuen
  14. Mone Zaidi
(2024)
An atlas of brain-bone sympathetic neural circuits in mice
eLife 13:e95727.
https://doi.org/10.7554/eLife.95727

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https://doi.org/10.7554/eLife.95727