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

Cell Rep. 2023 Apr 25;42(4):112295. doi: 10.1016/j.celrep.2023.112295. Epub 2023 Mar 21.

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-MafEX) 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-MafEX neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-MafEX 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-MafEX neuron activation. Our study identifies c-MafEX neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.

Keywords: CP: Neuroscience; allodynia,; allokinesis; corticospinal tract,; deep dorsal horn,; neuropathic pain,; nociception; protein kinase C gamma; spinal cord,; spinal interneurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Interneurons / physiology
  • Mice
  • Neuralgia*
  • Posterior Horn Cells / physiology
  • Proto-Oncogene Proteins c-maf
  • Spinal Cord
  • Spinal Cord Dorsal Horn* / pathology
  • Synaptic Transmission

Substances

  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf