Glucocorticoid-Dependent Hippocampal Transcriptome in Male Rats: Pathway-Specific Alterations With Aging

• Published in: Endocrinology (Philadelphia) Vol. 154; no. 8; pp. 2807 - 2820
• Main Authors: Chen, Kuey-Chu, Blalock, Eric M., Curran-Rauhut, Meredith A., Kadish, Inga, Blalock, Susan J., Brewer, Lawrence, Porter, Nada M., Landfield, Philip W.
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Oxford University Press 01.08.2013; Endocrine Society
• Subjects: Adrenalectomy; Aging; Aging - genetics; Alzheimer's disease; Animals; Biological and medical sciences; Biosynthesis; Blood levels; Body Weight - drug effects; Brain; CA1 Region, Hippocampal - metabolism; Cholesterol; Corticosterone; Corticosterone - blood; Corticosterone - pharmacology; DNA microarrays; Drinking - drug effects; Drug Implants; Eating - drug effects; Fundamental and applied biological sciences. Psychology; Gene expression; Gene regulation; Genes; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Glucocorticoid receptors; Glucocorticoids; Glucocorticoids - pharmacology; Glucose metabolism; Hippocampus; Hypotheses; Immunohistochemistry; Inflammation; Lipid metabolism; Male; Males; Neurodegenerative diseases; Neuroendocrinology; Neuronal-glial interactions; Oligonucleotide Array Sequence Analysis; Phenotypes; Rats; Rats, Inbred F344; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Transcriptome - drug effects; Transcriptomes; Vertebrates: endocrinology; Vertebrata; Mammalia; Rat; Animal; Ageing; Rodentia; Central nervous system; Alteration; Male; Glucocorticoid; Hippocampus; Encephalon
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2013-1139

Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor–activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between intermediate and low CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT–up-regulated genes included learning/plasticity, differentiation, glucose metabolism, and cholesterol biosynthesis, whereas processes overrepresented by CORT–down-regulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC transcriptome with a previously defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same direction, the majority were shifted in opposite directions by CORT and aging (eg, glial inflammatory genes down-regulated by CORT are up-regulated with aging). These results contradict the hypothesis that GCs simply promote brain aging and also suggest that the opposite direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways, whereas GC overstimulation develops in others, together generating much of the brain aging phenotype.