CRH neurons in the AM-ACC circuit drive chronic pain and anxiety comorbidity

Chronic pain induces anxiety disorders through aberrant interactions between the limbic system and sensory pathways, forming refractory comorbidity. The anterior cingulate cortex (ACC), a key hub for integrating pain and emotion, contains corticotropin-releasing hormone (CRH) neurons closely associated with stress responses. However, the thalamic input mechanisms mediating the pain and anxiety comorbidity remain unclear. Here, through immunofluorescence staining, calcium imaging, neural circuit tracing, patch-clamp recording, and optogenetics- or chemogenetics-based manipulations, we re-veal that the anteromedial thalamic nucleus (AM), as a pivotal nucleus of the anterior thalamic group, specifically regulates ACC^CRH neurons via a glutamatergic pathway, forming an AM^CaMKIIɑ-ACC^CRH neural circuit that collectively drives the progression of pain-anxiety comorbidity. This study is to elucidate the central role of the AM^CaMKIIɑ, ACC^CRH neurons, and AM^CaMKIIɑ-ACC^CRH neural circuit in encoding the emotional dimen-sion of pain. It provides a novel theoretical framework for targeting this neural circuit in the treatment of pain-anxiety comorbidity.