High-fat diets (HFDs) are a significant risk factor for various non-communicable diseases, including potential links to psychiatric disorders. While short-term HFD exposure in young animals may have beneficial effects on myelination and neuroplasticity, long-term consumption consistently correlates with cognitive and emotional impairments. The mechanisms behind these neurobehavioral alterations remain unclear. HFDs are known to impair autophagy in various peripheral tissues and suppress neuronal autophagy in the brain, impacting appetite, cognition, and mood. Defects in autophagy lead to neuronal degeneration, while autophagy-inducing drugs show antidepressant-like properties. Exercise is a well-established strategy for preventing and ameliorating depression and other HFD-related conditions. Exercise can activate autophagy, promoting tissue integrity and inhibiting inflammation. Previous research from the authors' group demonstrated treadmill training's ability to regulate the mTOR pathway and enhance synaptic plasticity. However, the complete cellular signaling mechanism by which exercise alleviates HFD-induced depression-like behavior, particularly the upstream mechanism of motor regulation of mTOR, has not been elucidated. The study hypothesizes that exercise training mediates the mTOR pathway, affecting hippocampal synaptic plasticity and alleviating HFD-induced depression-like behavior. This is tested using a mouse model of HFD-induced depression.

The literature extensively documents the adverse effects of long-term HFD consumption on various aspects of health, encompassing metabolic diseases, cognitive decline, and increased vulnerability to mental health disorders such as depression. Studies in both animals and humans demonstrate a strong association between HFDs and negative impacts on brain structure and function, often linked to inflammation and impaired neuronal function. Conversely, the benefits of regular physical exercise on mental and physical well-being are also well-established. The literature supports a role for exercise in improving mood and cognitive function, potentially by modulating neuroplasticity and cellular processes such as autophagy. Several studies have explored the impact of HFDs on autophagy in various tissues, highlighting its potential role in mediating HFD-related pathologies. Research also indicates a link between autophagy, synaptic plasticity, and the development of depressive-like behaviors. While previous studies have investigated the effects of exercise on autophagy, the precise mechanisms through which it interacts with HFD-induced neurobehavioral changes, especially in the context of depression, remain to be fully understood. This study aims to address this gap by focusing on the Wnt5a pathway, a key factor in mediating the crosstalk between neuronal activity, autophagy, and synaptic plasticity in the context of exercise and HFD-induced depression.

The study employed a mouse model to investigate the effects of exercise on HFD-induced depressive-like behaviors. Male C57BL/6J mice were randomly assigned to three groups: Control (standard chow), HFD (60% kcal from fat), and RUN (HFD + 1 hour of daily treadmill exercise for 8 weeks). Depressive-like behaviors were assessed using the tail suspension test (TST), forced swimming test (FST), sucrose preference test (SPT), and open field test (OFT). Hippocampal tissues were collected for RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). Immunofluorescence, Golgi staining, electron microscopy, and electrophysiological experiments were used to evaluate neuronal morphology, function, autophagy, and synaptic plasticity. A second experiment incorporated a Wnt5a inhibitor (Box5) to determine the role of Wnt5a in mediating the effects of exercise. Statistical analyses, including one-way and repeated-measures ANOVA, were used to compare among and within groups.

Exercise significantly attenuated HFD-induced depressive-like behaviors, as evidenced by reduced immobility time in TST and FST, improved sucrose preference, and increased locomotor activity and exploration in the OFT. Exercise also ameliorated HFD-induced hippocampal neuronal damage and neuroinflammation. RNA-seq revealed that exercise altered the expression of several hippocampal genes, with *Wnt5a* showing the strongest correlation with behavioral improvements. Exercise significantly increased Wnt5a and p-Camkll-α protein levels, which were reduced in the HFD group. Electrophysiological recordings showed that exercise enhanced excitatory postsynaptic currents (EPSCs) in the hippocampal CA1 region. Electron microscopy revealed that exercise increased the number of autophagosomes and autolysosomes, indicating enhanced neuronal autophagy. Golgi staining demonstrated that exercise prevented HFD-induced reductions in dendritic complexity and spine density. Western blotting confirmed that exercise increased Beclin 1 and LC3B-II levels while decreasing p62 and mTOR levels, all consistent with enhanced autophagy. The Wnt5a inhibitor Box5 counteracted the beneficial effects of exercise on depressive-like behaviors, autophagy, synaptic transmission, and synaptic remodeling. Box5 blocked the exercise-induced increase in Wnt5a and p-Camkll-α, reduced EPSC amplitude and frequency, decreased autophagosome numbers, and impaired synaptic structure.

The findings demonstrate that regular exercise effectively mitigates HFD-induced depressive-like behaviors and hippocampal neuronal damage in mice. The study identifies *Wnt5a* as a critical mediator of these effects, highlighting the involvement of the Wnt5a/Camkll signaling pathway in regulating neuronal autophagy and synaptic plasticity. Exercise-induced activation of this pathway leads to enhanced autophagy, promoting neuroprotection and reversing HFD-induced synaptic impairments. The results strongly support the hypothesis that exercise exerts its antidepressant-like effects, at least in part, by upregulating the Wnt5a/Camkll pathway, thereby enhancing neuronal autophagy and promoting synaptic remodeling. This study provides novel mechanistic insights into the beneficial effects of exercise on HFD-induced depression, suggesting potential therapeutic targets for interventions.

This study reveals a novel mechanism by which regular exercise ameliorates HFD-induced depressive-like behaviors. Exercise activates the Wnt5a/Camkll signaling pathway, leading to increased neuronal autophagy and enhanced synaptic plasticity in the hippocampus. The crucial role of Wnt5a in mediating these effects is demonstrated through the use of a Wnt5a inhibitor, which blocked the beneficial effects of exercise. These findings have important implications for developing non-pharmacological strategies to prevent and treat diet-induced neuropsychiatric disorders. Future research could explore the translational potential of this pathway as a therapeutic target and examine the long-term effects of exercise interventions.

The study used a mouse model, and the findings may not be directly generalizable to humans. The study focused primarily on neuronal mechanisms, and the involvement of other cell types (e.g., astrocytes, microglia) in mediating the effects of exercise requires further investigation. The study used a relatively short period of exercise training, and the long-term effects of exercise interventions warrant further examination. Finally, the study did not explore potential sex differences in the response to exercise and HFD.