Kappa-opioid receptor activation promotes depression-like behaviors by suppressing Pax6-dependent adult hippocampal neurogenesis.

Accumulating evidence indicates that adult hippocampal neurogenesis (AHN) undergoes heterogeneous alterations in depression, yet the underlying mechanisms remain incompletely understood. In this study, we established a corticosterone (CORT)-induced mouse model of depression and combined pharmacological, molecular biological, and genetic approaches to investigate the mechanisms through which CORT suppresses AHN and induces depressive-like behaviors. Our results demonstrated that chronic CORT treatment led to depressive-like phenotypes in mice, including decreased sucrose preference and behavioral despair, accompanied by impaired AHN, manifested by a reduction in immature neurons (DCX⁺BrdU⁺) but an increase in proliferating cells (Ki67⁺). Further mechanistic studies revealed that CORT upregulates dynorphin A in the dentate gyrus (DG), leading to overactivation of the κ-opioid receptor (KOR). This subsequently inhibits the expression of Pax6 and its downstream targets Neurog2 and NeuroD1, thereby obstructing neuronal differentiation. The KOR antagonist nor-BNI effectively reversed both the depressive-like behaviors and AHN abnormalities induced by CORT. Moreover, overexpression of Pax6 alleviated depressive behaviors and restored neurogenesis, whereas knockdown of Pax6 was sufficient to induce depressive phenotypes and impair AHN. Our study unveils a central role of the KOR/Pax6 signaling axis in AHN suppression and depression pathogenesis, providing a theoretical foundation for antidepressant strategies targeting KOR or Pax6.