A primary auditory cortex-anterior cingulate cortex circuit underlying cross-modal visceral pain modulation

Visceral pain represents an unmet clinical need due to the lack of safe and generalizable therapies. Given the analgesic potential of music and the underlying crosstalk between auditory and nociceptive pathways, this study aims to delineate the neural circuits interfacing auditory processing and visceral pain modulation. Using a mouse model of early-life stress, we identify a cortico-cortical circuit linking the primary auditory cortex (Au1) to the anterior cingulate cortex (ACC) that mediates stress-induced visceral pain. Mechanistically, early-life stress suppresses the activity of Au1 inhibitory (GABAergic, Au1GABA) neurons, which disinhibits downstream ACC excitatory (glutamatergic, ACCGlu) neurons, thereby driving visceral hypersensitivity. Notably, music intervention alleviates visceral pain by restoring Au1GABA neuronal activity and suppressing ACCGlu activity. In conclusion, this study unveils the Au1-ACC circuit as a critical hub for stress-induced visceral hypersensitivity and music-induced analgesia, providing a mechanistic foundation for clinical translation of music therapy in visceral pain management. This study presents the inhibitory primary auditory cortex – anterior cingulate cortex pathway underlying the auditory-pain crosstalk in mice, thus serving as a neural substrate for music therapy in visceral pain management.