1. Neuroscience

Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

  1. Robert Philip Ganley
  2. Marilia Magalhaes de Sousa
  3. Kira Werder
  4. Tugce Öztürk
  5. Raquel Mendes
  6. Matteo Ranucci
  7. Hendrik Wildner
  8. Hanns Ulrich Zeilhofer  Is a corresponding author
  1. University of Zurich, Switzerland
  2. University of Zürich, Switzerland
https://doi.org/10.7554/eLife.78689
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  1. Robert Philip Ganley
  2. Marilia Magalhaes de Sousa
  3. Kira Werder
  4. Tugce Öztürk
  5. Raquel Mendes
  6. Matteo Ranucci
  7. Hendrik Wildner
  8. Hanns Ulrich Zeilhofer
(2023)
Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn
eLife 12:e78689.
https://doi.org/10.7554/eLife.78689
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Abstract

Spinally-projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies and Tph2-Cre transgenic mice, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception. Our tracing experiments revealed that serotonergic neurons of the LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than medial hindbrain serotonergic neurons. Taking advantage of this difference, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and their impact on nociceptive sensitivity. The LPGi neurons that give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord appear to be ideally posed to contribute to widespread systemic pain control.

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All data generated or analysed during this study are included in the manuscript. Raw data acquired in these experiments are uploaded to www.datadryad.org and are available for download.

The following data sets were generated

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Author details

  1. Robert Philip Ganley

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8502-9870

  2. Marilia Magalhaes de Sousa

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Kira Werder

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Tugce Öztürk

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  5. Raquel Mendes

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  6. Matteo Ranucci

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. Hendrik Wildner

    Institute for Pharmacology and Toxicology, University of Zürich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  8. Hanns Ulrich Zeilhofer

    Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    For correspondence
    zeilhofer@pharma.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6954-4629

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_197888)

  • Hanns Ulrich Zeilhofer

Olga Mayenfisch Stiftung

  • Hendrik Wildner

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

Reviewing Editor

  1. David D Ginty, Harvard Medical School, United States

Ethics

Animal experimentation: Permission to perform these experiments was obtained from the Veterinäramt des Kantons Zürich (154/2018 and 063/2016)

Version history

  1. Received: March 16, 2022
  2. Preprint posted: March 18, 2022 (view preprint)
  3. Accepted: February 6, 2023
  4. Accepted Manuscript published: February 8, 2023 (version 1)
  5. Version of Record published: February 21, 2023 (version 2)

Copyright

© 2023, Ganley 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. Robert Philip Ganley
  2. Marilia Magalhaes de Sousa
  3. Kira Werder
  4. Tugce Öztürk
  5. Raquel Mendes
  6. Matteo Ranucci
  7. Hendrik Wildner
  8. Hanns Ulrich Zeilhofer
(2023)
Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn
eLife 12:e78689.
https://doi.org/10.7554/eLife.78689

Share this article

https://doi.org/10.7554/eLife.78689

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