Differentially expressed genes accompanying neurobehavioral deficits in a modified rat model of vascular dementia

Abstract

Vascular dementia refers to the progressive loss of memory and other cognitive functions. The heterogeneity of cerebrovascular disease renders it challenging to elucidate the neuropathological substrates and mechanisms underlying vascular dementia. In this study, we performed neurobehavioral tests, RNA sequencing (RNA-seq), and quantitative real-time polymerase chain reaction (qRT-PCR) tests to evaluate a rat model of modified two-vessel occlusion (2-VO) and identify the differentially expressed genes in the hippocampus of 2-VO versus sham rats by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Compared with the sham group, the 2-VO group revealed significantly reduced spontaneous motor behaviors, a lack of exploration for new objects, and varying degrees of spatial memory impairment. Although the genetic background of vascular dementia is well established for monogenic disorders, the relationship between key regulatory genes and signaling pathways remains obscure. Using RNA-seq and bioinformatic analyses, we identified 58 upregulated genes and 137 downregulated genes in the hippocampus of 2-VO rats compared to sham rats. Results were confirmed by qRT-PCR. ErbB3, a gene mainly involved in cranial nervous system development, negative regulation of neuronal apoptosis, and signal transduction, was downregulated in the hippocampus of 2-VO rats compared to sham rats. Moreover, ERBB3 plays an important role in neuron-protecting ERBB and PI3K-AKT signaling pathways, both of which were found to be enriched by GO and KEGG functional pathway analyses. Understanding the molecular mechanisms of vascular dementia may help establish potential treatment targets for cognitive deficits.