To investigate the effects of alcohol dependence (with high-fat) on the morphology and structure of rat hippocampal cells as well as learning and memory abilities, and to explore the role played by FoxO3a-Smad4-regulated autophagy. The hippocampal neurons and synaptic ultrastructure were observed by using eosin-s hematoxylin staining and transmission electron microscopy, the expression levels of hippocampal FoxO3a, Smad4 and autophagy proteins were detected by Western blotting, and the co-localisation of FoxO3a and Smad4 was observed by laser confocal. Alcohol dependence was associated with the development of cognitive impairment, resulting in pathological changes in hippocampal neurons and altered synaptic plasticity in cognition-related brain regions, while alcohol + high-fat increased the risk of cognitive impairment, with the increase of ingested alcohol concentration and the increase of high-fat dietary intake, the rats' learning and memory abilities were significantly reduced. The present findings suggest that alcohol dependence combined with a high-fat diet is associated with cognitive impairment, hippocampal neuronal and synaptic damage, and alterations in FoxO3a-Smad4 expression and autophagy markers in rats. These changes potentially involving the TGF-β1/FoxO3a-Smad signalling axis and associated alterations in autophagy markers. Further causal studies are warranted to determine the precise functional contribution of this axis.
