Abstract
ObjectiveThis study systematically investigated the effect of chronic stress on the hippocampus and its damage mechanism at the whole genome level.MethodsThe rat whole genome expression chips (Illumina) were used to detect gene expression differences in the hippocampus of rats subjected to chronic immobilization stress (daily immobilization stress for 3 h, for 7 or 21 days). The hippocampus gene expression profile was studied through gene ontology and signal pathway analyses using bioinformatics. A differentially expressed transcription regulation network was also established. Real-time quantitative polymerase chain reaction (RT-PCR) was used to verify the microarray results and determine expression of the Gabra1, Fadd, Crhr2, and Cdk6 genes in the hippocampal tissues.ResultsCompared to the control group, 602 differentially expressed genes were detected in the hippocampus of rats subjected to stress for 7 days, while 566 differentially expressed genes were expressed in the animals experiencing stress for 21 days. The stress significantly inhibited the primary immune system functions of the hippocampus in animals subjected to stress for both 7 and 21 days. Immobilization activated the extracellular matrix receptor interaction pathway after 7 day exposure to stress and the cytokine-cytokine receptor interaction pathway. The enhanced collagen synthesis capacity of the hippocampal tissue was the core molecular event of the stress regulation network in the 7-day group, while the inhibition of hippocampal cell growth was the core molecular event in the 21-day group. For the Gabra1, Fadd, Crhr2, and Cdk6 genes, RT-PCR results were nearly in line with gene chip assay results.ConclusionDuring the 7-day and 21-day stress processes, the combined action of polygenic, multilevel, and multi-signal pathways leads to the disorder of the immunologic functions of the hippocampus, hippocampal apoptosis, and proliferation disequilibrium.
Highlights
Stress response is characterized by the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the subsequent increase in glucocorticoid (GC) secretion
Real-time qPCR was adopted to verify the up-regulation of Gabra1 and Fadd gene expressions and the down-regulation of Crhr2 and cyclin-dependent kinase 6 (Cdk6) gene expression
We focused on sequences from the 3000 bp upstream of the transcription start site (TSS) to 500 bp downstream and used them for transcription factor binding site (TFBS) motif discovery
Summary
Stress response is characterized by the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the subsequent increase in glucocorticoid (GC) secretion. HPA axis activation is an important adaptive and protective response to stress. In the chronic stress process, the HPA axis is usually in a continuous high-response state, leading to increased GC and functional disorders of the nervous, endocrine, and immune systems, among others. The hippocampus is the key brain region related to learning, memory, cognition, and emotion. It is one of the most important encephalic regions that mediate stress reaction. Several studies have reported on the mechanism by which stress affects the functions of the hippocampus at the single gene level. Investigations on the mechanism by which stress affects the function of the hippocampus at the whole genome level are lacking
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