Anterior insular CB1 receptor signaling selectively regulates social novelty and anxiety-related behaviors

Abstract Several neurodevelopmental disorders (NDDs) are characterized by impairments in social behavior and affective dysregulation. Converging evidence implicates the endocannabinoid system in the control of both behaviors. However, the brain region-specific contribution of cannabinoid receptor type 1 (CB1R) signaling to these NDD-relevant phenotypes remains unclear. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing and social novelty recognition. Whether CB1Rs within this region are sufficient to regulate behavioral domains disrupted in NDDs remains unclear. Here, we employed a Cre-dependent viral strategy to selectively restore CB1R mRNA expression in the aINS of global CB1R-deficient mice. Region-specific rescue of CB1R in the aINS normalized social novelty discrimination and reduced anxiety-like behavior as compared to mice lacking CB1R, while leaving basal sociability and locomotor activity unaffected. In addition, insular CB1R re-expression modulated repetitive-like behaviors without broadly altering other behavioral domains. These effects were observed in the absence of off-target expression, supporting the specificity of the genetic manipulation. Our findings demonstrate that CB1R mRNA expression within the aINS is sufficient to regulate distinct socio-emotional and repetitive behavioral domains. These results identify the aINS as a critical CB1-dependent modulatory node and provide mechanistic insight into how region-specific endocannabinoid signaling contributes to behavioral phenotypes relevant to NDDs.