Insular cortex-lateral habenula circuit mediates chronic itch-associated affective comorbidities.

Pruritus triggers scratching-induced skin damage and anxiety/depression, forming a vicious cycle that exacerbates inflammatory skin diseases. The insular cortex (IC) integrates itch and emotional processing, while the lateral habenula (LHb) regulates depression.Using acute (3-day) and chronic (14-day) histamine-induced murine itch models combined with chemogenetic manipulation, we demonstrate that the insular cortex (IC) bidirectionally regulates acute itch and anxiety-like behaviors, whereas chronic itch engages the IC-lateral habenula (LHb) circuit to drive comorbid depression. These results establish the IC-LHb circuit as a critical mechanistic driver of chronic itch-associated affective comorbidities. They further highlight serotonergic modulation of this pathway as a promising therapeutic strategy for neuroinflammatory itch.