Tas2r123-associated mitochondrial organization and neuroplasticity underlying the antidepressant effect of resveratrol

Resveratrol, a natural bitter polyphenol, exhibits significant antidepressant property. Numerous studies have linked its antidepressant effect to neuroplasticity enhancement or mitochondrial regulation. However, the interplay between these two mechanisms remains unclear. This study aims to elucidate the relationship among resveratrol's antidepressant effect, its regulatory impact on neuroplasticity and mitochondrial function, and to investigate the potential role of the type 2 bitter taste receptors (Tas2rs) in these processes. A chronic unpredictable mild stress (CUMS) model was used to induce depressive-like behaviors, while resveratrol was administered as an intervention. Following CUMS and resveratrol treatment, proteomic analysis combined with bioinformatics predicted significantly altered biological pathways in the hippocampus. The aforementioned predictions were validated using Western blotting (WB), Golgi staining, Nissl staining, and electron microscopy. Additionally, Tas2rs expression and calcium (Ca2+) levels in the hippocampus were quantified using quantitative PCR, WB, and calcium assay kit. Finally, immunofluorescence (IF) colocalization was used to examine the association of Tas2r123 with mitochondrial outer membrane in hippocampus. Resveratrol significantly alleviated depressive-like behaviors induced by CUMS. Proteomic analysis revealed that resveratrol's therapeutic effects are associated with neuroplasticity-related and metabolic pathways, particularly with differentially expressed proteins (DEPs) predominantly localized in the mitochondria. Gene Ontology analysis of mitochondrial DEPs further revealed substantial changes in mitochondrial organization. Furthermore, molecular biology experiments validated these proteomics findings. Additionally, resveratrol also reversed the CUMS-induced downregulation of Tas2r123 mRNA and protein expression. Moreover, IF colocalization demonstrated a strong association between Tas2r123 and mitochondria. Our findings suggest that resveratrol may exert antidepressant property by modulating neuroplasticity through the Tas2r123-mitochondrial organization pathway. This study introduces a novel perspective linking Tas2rs to resveratrol's antidepressant mechanisms, potentially pave the way for future antidepressant therapies.