An inhibitory circuit from central amygdala to zona incerta drives pain-related behaviors in mice
- National Center for Complementary and Integrative Health, United States
- 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
Yarimar Carrasquillo
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.
Reviewing Editor
- Matthew N Hill, University of Calgary, Canada
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).
Version history
- Preprint posted: March 12, 2021 (view preprint)
- Received: March 24, 2021
- Accepted: October 20, 2022
- Accepted Manuscript published: October 21, 2022 (version 1)
- Version of Record published: November 4, 2022 (version 2)
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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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
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