Environmental enrichment reverses ELS-induced visceral pain and depression through a prefrontal-limbic circuit involving CB1Rs.

Neonatal colorectal distension (CRD), as a mechanical stress stimulus in early life to simulate irritable bowel syndrome (IBS), increases susceptibility to visceral pain and depression-like behaviors in adulthood. Enriched environment (EE) treatment effectively counteracts these effects, but the underlying neural circuit and molecular mechanisms remain poorly defined. Here, we investigate whether EE reverses visceral pain and depression by modulating cannabinoid type-1 receptors (CB1Rs) in the PrLGlu→avBNST pathway. A multidisciplinary combination of behaviors, chemogenetics, optogenetics, pharmacology, molecular and electrophysiological approaches is applied. In CRD rats, CB1Rs-expressing glutamatergic neurons in prelimbic cortex (PrL) projecting to the anteroventral bed nucleus of the stria terminalis (avBNST) promote visceral pain and depression. EE exerts analgesic and antidepressant effects by rescuing PrLGlu→avBNSTGABA pathway activity and reducing CB1Rs expression. EE also reverses the CRD-induced paraventricular nucleus (PVN) hyperactivity by reversing the dysfunction of this pathway. Together, EE alleviates chronic visceral pain and comorbid depression by restoring homeostasis in the CB1Rs-modulated PrLGlu→avBNSTGABA→PVN pathway. Combining EE and CB1Rs-targeted pharmacological modulation offers a promising therapeutic strategy for early-life developmental disorder-related pain-depression comorbidities.