Dissociable Control of Depression and Visceral Pain by the Picglu-Avbnst Circuit in Male Mice with Chronic Colitis.

Comorbid depressive symptoms are highly prevalent in patients with chronic colitis, posing a major clinical challenge because pain and depression often fail to respond to the same treatment. However, the neural mechanisms underlying this comorbidity remain poorly understood. Using a dextran sulfate sodium (DSS)-induced chronic colitis mouse model, we identified depression-resilient and depression-susceptible phenotypes and uncovered a critical role for the posterior insular cortex glutamatergic (pICGlu) projection to the anteroventral bed nucleus of the stria terminalis (avBNST) in regulating both depressive-like behaviors and visceral hypersensitivity. Bidirectional chemogenetic manipulation of pICGlu neurons and optogenetic modulation of the pICGlu-avBNST circuit revealed dissociable control of affective and sensory processing: activation alleviated depressive-like behaviors but enhanced visceral pain sensitivity, whereas inhibition produced the opposite effects. Furthermore, genetic and pharmacological manipulation of CB1R signaling influenced depression-like behaviors and visceral hypersensitivity in chronic colitis. Together, these findings identify the pICGlu-avBNST circuit and support a role for CB1R signaling in the affective and sensory abnormalities associated with chronic colitis, with mechanistic studies performed in male mice.