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

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 mechan-ical 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 path-ological pain signaling upon loss of inhibitory control.

Automated summary

CST neurons innervate spinal dorsal horn and play a role in chronic neuropathic pain. Interneurons expressing c-Maf are targeted by CST neurons. Excitatory c-Maf neurons mainly receive sensory input from myelinated fibers, and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons. Silencing c-Maf neurons reduces mechanical hypersensitivity in neuropathic mice. c-Maf neurons also receive input from inhibitory c-Maf and parvalbumin neurons. Disrupting inhibition from these neurons causes mechanical hypersensitivity and spontaneous aversive behaviors similar to c-Maf neuron activation. c-Maf neurons become engaged in pathological pain signaling when inhibitory control is lost.