Regular exercise ameliorates high-fat diet-induced depressive-like behaviors by activating hippocampal neuronal autophagy and enhancing synaptic plasticity
Jialin Wu, Huachong Xu, Shiqi Wang, Huandi Weng, Zhihua Luo, Guosen Ou, Yaokang Chen, Lu Xu, Kwok‐Fai So, Li Deng, Li Zhang, Xiaoyin Chen
Abstract
Exercise enhances synaptic plasticity and alleviates depression symptoms, but the mechanism through which exercise improves high-fat diet-induced depression remains unclear. In this study, 6-week-old male C57BL/6J mice were administered a high-fat diet (HFD, 60% kcal from fat) to a HFD model for 8 weeks. The RUN group also received 1 h of daily treadmill exercise in combination with the HFD. Depressive-like behaviors were evaluated by behavioral assessments for all groups. The key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors was detected by RNA-seq. The morphology and function of the neurons were evaluated via Nissl staining, Golgi staining, electron microscopy and electrophysiological experiments. The results showed that exercise attenuated high-fat diet-induced depressive-like behavior and reversed hippocampal gene expression changes. RNA-seq revealed Wnt5a, which was a key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors. Further work revealed that exercise significantly activated neuronal autophagy in the hippocampal CA1 region via the Wnt5a/CamkII signaling pathway, which enhanced synaptic plasticity to alleviate HFD-induced depressive-like behavior. However, the Wnt5a inhibitor Box5 suppressed the ameliorative effects of exercise. Therefore, this work highlights the critical role of Wnt5a, which is necessary for exercise to improve high-fat diet-induced depression.