Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn
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.
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.
Targeted Anatomical and Functional Identification of Antinociceptive and Pronociceptive Serotonergic Neurons that Project to the Spinal Dorsal HornDryad Digital Repository, doi:10.5061/dryad.h70rxwdm9.
Article and author information
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.
Animal experimentation: Permission to perform these experiments was obtained from the Veterinäramt des Kantons Zürich (154/2018 and 063/2016)
- David D Ginty, Harvard Medical School, United States
- Received: March 16, 2022
- Preprint posted: March 18, 2022 (view preprint)
- Accepted: February 6, 2023
- Accepted Manuscript published: February 8, 2023 (version 1)
- Version of Record published: February 21, 2023 (version 2)
© 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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