Abstract
11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) locally regenerates active glucocorticoids from their inert forms thereby amplifying intracellular levels within target tissues including the brain. We previously showed greater increases in intra‐hippocampal corticosterone (CORT) levels upon Y‐maze testing in aged wild‐type than in 11β‐HSD1−/− mice coinciding with impaired and intact spatial memory, respectively. Here we examined whether ageing influences 11β‐HSD1 regulation of CORT in the dorsal hippocampus under basal conditions during the diurnal cycle and following stress. Intra‐hippocampal CORT levels measured by in vivo microdialysis in freely behaving wild‐type mice displayed a diurnal variation with peak levels in the evening that were significantly elevated with ageing. In contrast, the diurnal rise in intra‐hippocampal CORT levels was greatly diminished in 11β‐HSD1−/− mice and there was no rise with ageing; basal intra‐hippocampal CORT levels were similar to wild‐type controls. Furthermore, a short (3 min) swim stress induced a longer lasting increase in intra‐hippocampal CORT levels in wild‐type mice than in 11β‐HSD1−/− mice despite no genotypic differences in elevation of plasma CORT. These data indicate that 11β‐HSD1 activity contributes substantially to diurnal and stress‐induced increases in hippocampal CORT levels. This contribution is even greater with ageing. Thus, 11β‐HSD1 inhibition may be an attractive target for treating cognitive impairments associated with stress or ageing.
Highlights
Glucocorticoids are potent modulators of mood and memory (De Kloet et al, 1998; de Quervain et al, 2009)
CORT circulates mostly bound to corticosteroid-binding globulin (CBG), with the remaining free CORT fraction readily reaching the brain where it binds to intracellular receptors, the high-affinity mineralocorticoid receptors and lower affinity glucocorticoid receptors (GRs; Herman et al, 1989; de Kloet et al, 1993)
While elevated circulating CORT levels associated with ageing have been widely shown to impair hippocampus-dependent spatial memory in rodents (Issa et al, 1990; Yau et al, 1995; Vallee et al, 1999), our studies support a central role of 11b-HSD1-generated CORT in this process (Yau & Seckl, 2012)
Summary
Glucocorticoids are potent modulators of mood and memory (De Kloet et al, 1998; de Quervain et al, 2009). CORT circulates mostly bound to corticosteroid-binding globulin (CBG), with the remaining free CORT fraction readily reaching the brain where it binds to intracellular receptors, the high-affinity mineralocorticoid receptors and lower affinity glucocorticoid receptors (GRs; Herman et al, 1989; de Kloet et al, 1993) Both receptors are abundant in limbic regions of the brain, in the hippocampus, a structure known to play a critical role in memory (McEwen & Sapolsky, 1995; Barbosa et al, 2012) and in the HPA axis stress response (Herman et al, 2005). We found that intra-hippocampal CORT levels rise rapidly during the acquisition and retrieval trials in the Y-maze spatial memory task, and that it is the 11bHSD1-generated CORT from this rise during retrieval that associates with impaired memory in aged wild-type mice (Yau et al, 2015) This suggests a dynamic regulation of intracellular CORT by 11bHSD1 as required during periods of enhanced HPA axis activity
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