Cross-modal cortical circuit for sound sensitivity in neuropathic pain.

Abstract

Hyperacusis, exaggerated sensitivity to sound, frequently accompanies chronic pain in humans, suggesting interactions between different sensory systems in the brain. However, the neural mechanisms underlying this comorbidity remain largely unexplored. In this study, behavioral tests measuring sound-evoked pupil dilation and reaction times to lick water following auditory stimuli showed hyperacusis-like behaviors in neuropathic pain model mice. Through viral tracing, fiber photometry, and multi-electrode recordings, we identified glutamatergic projections from primary somatosensory cortex (S1HL^Glu) to the auditory cortex (ACx) that participate in amplifying sound-evoked neuronal activity following spared nerve injury in the hindlimb. Chemo- or optogenetic manipulation and electrophysiology recordings confirmed that the S1HL^Glu → ACx pathway is essential for this heightened response to sound. Specifically, activating this pathway intensified glutamatergic neuronal activity in the ACx and induced hyperacusis-like behaviors, while chemogenetic suppression reversed these effects in neuropathic pain model mice. These findings illustrate the mechanism by which central gain increases in the ACx of neuropathic pain mice, improving our understanding of cross-modal sensory system interactions and suggesting circuit pathway targets for developing interventions to treat pain-associated hyperacusis in clinic.