An inhibitory circuit from central amygdala to zona incerta drives pain-related behaviors in mice

  1. Sudhuman Singh
  2. Torri D Wilson
  3. Spring Valdivia
  4. Barbara Benowitz
  5. Sarah Chaudhry
  6. Jun Ma
  7. Anisha P Adke
  8. Omar Soler-Cedeno
  9. Daniela Velasquez
  10. Mario A Penzo
  11. Yarimar Carrasquillo  Is a corresponding author
  1. National Center for Complementary and Integrative Health, United States
  2. National Institute of Mental Health, United States

Abstract

Central amygdala neurons expressing protein kinase C-delta (CeA-PKCδ) are sensitized following nerve injury and promote pain-related responses in mice. The neural circuits underlying modulation of pain-related behaviors by CeA-PKCδ neurons, however, remain unknown. In this study, we identified a neural circuit that originates in CeA-PKCδ neurons and terminates in the ventral region of the zona incerta (ZI), a subthalamic structure previously linked to pain processing. Behavioral experiments show that chemogenetic inhibition of GABAergic ZI neurons induced bilateral hypersensitivity in uninjured mice and contralateral hypersensitivity after nerve injury. In contrast, chemogenetic activation of GABAergic ZI neurons reversed nerve injury-induced hypersensitivity. Optogenetic manipulations of CeA-PKCδ axonal terminals in the ZI further showed that inhibition of this pathway reduces nerve injury-induced hypersensitivity whereas activation of the pathway produces hypersensitivity in the uninjured paws. Altogether, our results identify a novel nociceptive inhibitory efferent pathway from CeA-PKCδ neurons to the ZI that bidirectionally modulates pain-related behaviors in mice.

Data availability

All data generated during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-8 (including supplemental figures).

Article and author information

Author details

  1. Sudhuman Singh

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Torri D Wilson

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Spring Valdivia

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Barbara Benowitz

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sarah Chaudhry

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jun Ma

    National Institute of Mental Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anisha P Adke

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5062-3319
  8. Omar Soler-Cedeno

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5897-4156
  9. Daniela Velasquez

    National Center for Complementary and Integrative Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Mario A Penzo

    National Institute of Mental Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5368-1802
  11. Yarimar Carrasquillo

    National Center for Complementary and Integrative Health, Bethesda, United States
    For correspondence
    yarimar.carrasquillo@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0702-4975

Funding

National Center for Complementary and Integrative Health (Intramural Research Program)

  • Yarimar Carrasquillo

National Institute of Mental Health (Intramural Research Program)

  • Mario A Penzo

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

Ethics

Animal experimentation: Animal experimentation: All experiments were approved by the Animal Care and Use Committee of the National Institute of Neurological Disorders and Stroke and the National Institute on Deafness and other Communication Disorders with the guidelines set by the National Institutes of Health (ASP1397).

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Sudhuman Singh
  2. Torri D Wilson
  3. Spring Valdivia
  4. Barbara Benowitz
  5. Sarah Chaudhry
  6. Jun Ma
  7. Anisha P Adke
  8. Omar Soler-Cedeno
  9. Daniela Velasquez
  10. Mario A Penzo
  11. Yarimar Carrasquillo
(2022)
An inhibitory circuit from central amygdala to zona incerta drives pain-related behaviors in mice
eLife 11:e68760.
https://doi.org/10.7554/eLife.68760

Share this article

https://doi.org/10.7554/eLife.68760

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