Rheb in central amygdala somatostatin neurons regulates chronic itch and anxiety-like behaviors

Chronic itch represents a significant clinical challenge that substantially impairs patients' quality of life, yet its underlying neural circuit and molecular mechanisms remain elusive. Here, we demonstrate that somatostatin-expressing (SST) neurons in the central amygdala (CeA) are activated and functionally required in a mouse model of diphenylcyclopropenone (DCP)-induced chronic itch. Transcriptomic profiling further revealed upregulation of Ras homolog enriched in brain (Rheb) within DCP-TRAPed CeA SST neurons. Notably, Rheb knockdown suppressed the hyperexcitability of CeA SST neurons and alleviated chronic itch-related scratching and anxiety-like behaviors in DCP-treated mice. Conversely, Rheb overexpression promoted scratching and anxiety-like behaviors in naive mice. Collectively, these findings delineate a Rheb-regulated CeA SST neuronal mechanism that contributes to chronic itch-related scratching and anxiety-like behaviors, highlighting a potential molecular target for therapeutic intervention in chronic itch.