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

Abstract

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.

Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat

“…Finally, we examined the mRNA level of glial fibrillary acidic protein (GFAP) that has been shown to be repressed by CORT and upregulated by aging [45]. We confirmed that the GFAP mRNA was increased in aged AL animals (p < 0.05), and that EOD feeding counteracted this change, reverting the expression of GFAP mRNA to the level measured in 6-month-old control animals (Fig.…”

Aging, glucocorticoids and developmental programming

“…There is support for the view that glucocorticoids accelerate aging processes (Anderson et al 2014) as well as for development of both glucocorticoid resistance and glucocorticoid enhanced aging in different metabolic pathways (Chen et al 2013). We propose that circulating glucocorticoids follow an age-related trajectory, which can be affected by both the external environment and internal physiological events.…”

Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice

“…Growing studies have linked the stress level of GCs with neurodegenerative diseases, such as AD and depression vulnerability (Chen et al, 2013;Sotiropoulos et al, 2011). It has been reported that elevated levels of GCs have deleterious effects on the structure and function of neurons, and can even cause hippocampal cell death (Conrad et al, 2007;Csernansky et al, 2006;Kleen et al, 2006).…”