title: Diurnal and stress-induced intra-hippocampal corticosterone rise attenuated in 11β-HSD1-deficient mice: a microdialysis study in young and aged mice.
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.
authors.affiliation: Centre for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; Endocrinology Unit, BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Joyce L W
authors.initials: JL
authors.lastname: Yau
authors.forename: June
authors.initials: J
authors.lastname: Noble
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.forename: Mike
authors.initials: M
authors.lastname: Ludwig
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000502:physiology*; D000375:Aging; D000818:Animals; D002940:Circadian Rhythm; D003345:Corticosterone / Q000032:analysis / Q000502:physiology*; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D013315:Stress, Psychological
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone
keywords: ageing; glucocorticoids; hippocampus; hypothalamic-pituitary-adrenal axis