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c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy

Frezel, Noémie; Ranucci, Matteo; Foster, Edmund; Wende, Hagen; Pelczar, Pawel; Mendes, Raquel; Ganley, Robert P; Werynska, Karolina; d'Aquin, Simon; Beccarini, Camilla; Birchmeier, Carmen; Zeilhofer, Hanns Ulrich; Wildner, Hendrik (2023). c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy. Cell Reports, 42(4):112295.

Abstract

Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-Maf$^{EX}$) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-Maf$^{EX}$ neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-Maf$^{EX}$ neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-Maf$^{EX}$ neuron activation. Our study identifies c-Maf$^{EX}$ neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:English
Date:1 April 2023
Deposited On:06 Apr 2023 09:32
Last Modified:29 Jan 2025 02:35
Publisher:Cell Press (Elsevier)
ISSN:2211-1247
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.celrep.2023.112295
PubMed ID:36947543
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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