Background: Depression is an independent risk factor for atherosclerosis (AS), which can increase the risk of death and disability from AS. However, the mechanism of AS comorbidity with depression is complex. Methods: ApoE(-/-) and C57BL/6J mice were fed with a high-fat diet (model group, N=12 (sic)) and a normal diet (control group, N=12 (sic)). During the 15-week experimental period, the following tests were performed: coat color score, body weight, and sucrose preference tests (every 2 weeks); open-field test (1st, 7th, and 15th weeks); and light/dark and tail suspension tests (15th week). Oil Red O and hematoxylin and eosin (HE) stainings were used to assess the area of atherosclerotic status. The levels of triglyceride and total and low-density lipoprotein cholesterol in the serum and secretion of pro-inflammatory cytokines were determined using the enzyme-linked immunosorbent assay. The differentially expressed genes (DEGs) in the hippocampus and prefrontal cortex were screened by RNA-sequencing (RNA-seq) and analyzed using the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Results: Our findings showed that compared with C57 mice in the control group, ApoE(-/-) mice in the model group gradually developed depression-like behavioral changes with elevated blood lipid concentrations, serum inflammatory factor levels, and atherosclerotic plaque formation in the thoracic aorta. Consequently, in the RNA-seq and bioinformatics analysis, the high expression of inflammatory chemokine genes was found in the hippocampus and prefrontal cortex area. The regulation of movement, feeding, and reproduction of the gene expression decreased. Conclusions: These results indicate that when ApoE(-/-) mice were fed a high-fat diet for 15 weeks, depression-like behavioral changes occurred with the formation of atherosclerotic lesions. The RNA-seq, combined with bioinformatics analysis, showed that this AS comorbidity with depressive behavior was associated with the high expression of inflammation-related genes and pathways in the hippocampus and prefrontal cortex.
