Gastrodin enhances stress resilience through promoting Wnt/β-Catenin-dependent neurogenesis

• Gastrodin enhances stress resilience in mice. • Gastrodin protects adult hippocampal neurogenesis from chronic stress. • Wnt/β-catenin-dependent neurogenesis mediates gastrodin’s effects. Enhancing stress resilience constitutes a pivotal strategy in mitigating the risk of depression, making it a critical component of both prevention and treatment. In the current work, we identified a compound, gastrodin (GAS), as capable of enhancing stress resilience, as demonstrated by its ability to protect against depression following chronic stress exposure. To elucidate the potential of GAS to promote neurogenesis under chronic stress, along with the associated cellular and molecular processes involved. We evaluated the effect of GAS on NSPC proliferation and differentiation using both in vitro and in vivo investigations. Neurogenesis was inhibited using temozolomide to verify GAS’s impact on stress resilience. Comprehensive methodologies, including hippocampal transcriptome analysis and western blotting, were utilized to identify the involvement of the Wnt/β-catenin pathway. Immunolocalization was conducted to confirm β-catenin’s nuclear translocation in SOX2 + cells within the hippocampal dentate gyrus subgranular zone. GAS demonstrated robust stimulation of NSPC proliferation and neuronal differentiation, enhancing adult hippocampal neurogenesis under conditions of chronic stress. Inhibition of neurogenesis negated GAS’s protective effects on stress resilience. Integrated analysis pointed to the Wnt/β-catenin signaling pathway within NSPCs as a crucial mechanism facilitating GAS-promoted neurogenesis. Inhibiting Wnt expression or blocking β-catenin’s nuclear translocation abolished GAS’s neurogenic and stress-resilience enhancing effects. These results suggested that GAS directly activates the Wnt/β-catenin signaling pathway, which promotes the proliferation and neuronal differentiation of NSPCs, thereby enhancing adult hippocampal neurogenesis and promoting stress resilience to mitigate the risk of depression.