c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy
Noémie Frezel, Matteo Ranucci, Edmund Foster, Hagen Wende, Paweł Pelczar, Raquel Mendes, Robert P. Ganley, Karolina Werynska, Simon d‘Aquin, Camilla Beccarini, Carmen Birchmeier, Hanns Ulrich Zeilhofer, Hendrik Wildner
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.