A cortical-subcortical circuit underlies pain sensitization driven by sleep deprivation

Sleep disorders cause pain, yet the underlying neural circuits remain largely unknown. Using brain-wide neural tracing, optogenetics, chemogenetics, in vivo fiber photometry, and electrophysiological recording, we identified a retrosplenial cortex (RSC)-anterior cingulate cortex (ACC)-zona incerta (ZI) circuit mediating sleep loss-induced pain hypersensitivity. Nine hours of sleep deprivation (SD) triggered pain by activation of ACC neurons, whereas optogenetic inhibition of ACC^Glu neurons relieved SD-induced pain. Viral tracing identified RSC and ZI as key upstream and downstream regions for ACC. RSC^Glu inputs enhanced ACC^Glu activity, and chemogenetic manipulation of the RSC^Glu-ACC^Glu circuit induced pain in naive mice and relieved SD-induced pain. ACC^Glu neurons densely innervate ZI, activating ZI^GABA neurons after SD. Inhibiting the ACC^Glu-ZI^GABA circuit attenuated SD-induced pain, and ablation of ACC^Glu neurons reversed RSC^Glu-ACC^Glu-mediated pain. Together, these findings uncover a previously unrecognized neural circuit encoding sleep loss-induced pain.