Transforming Growth Factor-Beta/Smad Pathway in the Prefrontal-Hippocampal Loop in RatsTransforming growth factor-beta/Smad pathway plays an important role in the pathogenesis of neurological diseases. This study investigated the effects of high fat diet and alcohol dependence on memory and expression of transforming growth factor-beta/Smad in the prefrontal lobe, hippocampus and cerebellum of rats. Sixty male Sprague Dawley rats were randomly divided into control group, alcohol group and alcohol+highfat diet group. Morris water maze test was performed at 4 w, 8 w and 12 w after modeling, respectively. The prefrontal cortex, hippocampus and cerebellum were dissected for hematoxylin and eosin staining and transforming growth factor-beta 1 levels were detected by enzyme-linked immunosorbent assay. Western blotting was used to detect phospho-Smad3 and Smad4 levels. At 4 w, 8 w and 12 w of modeling, compared with the control group, the incubation period of rats in the alcohol group and the alcohol+high-fat diet group was prolonged and the prefrontal cone cells and Purkinje cells in the cerebellum were reduced to varying degrees and the cells were deformed. The expression levels of transforming growth factor-beta 1, phospho-Smad3 and Smad4 were significantly higher than those of the control group at 8 w and 12 w of modeling (p<0.05). High fat diet and alcohol may affect the function of cerebellum transforming growth factor-beta 1, phospho-Smad3 and Smad4 by enhancing the expression of transforming growth factor-beta 1, phospho-Smad3 and Smad4, leading to the decrease of spatial learning and memory ability in rats.