Abstract
High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design.Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals.
Highlights
Prolonged exposure to elevated glucocorticoids as a consequence of increased hypothalamic pituitary adrenal (HPA) axis activity during ageing associates with impaired hippocampal synaptic plasticity and spatial memory decline in rodents (Issa et al, 1990; VanGuilder et al, 2011) and in humans (Dodt et al, 1994; Lupien et al, 1998)
Plasma CORT levels are unaltered with 11b-HSD1 inhibition
We recently found that 10 days of UE2316 treatment reduced the dynamic rise in intrahippocampal CORT levels during memory retrieval in a Y-maze, an effect associated with improved spatial memory retention (Yau et al, in press)
Summary
Prolonged exposure to elevated glucocorticoids as a consequence of increased hypothalamic pituitary adrenal (HPA) axis activity during ageing associates with impaired hippocampal synaptic plasticity and spatial memory decline in rodents (Issa et al, 1990; VanGuilder et al, 2011) and in humans (Dodt et al, 1994; Lupien et al, 1998). Mainly from animal studies, suggest that age-related spatial memory impairments result from the cumulative effects of elevated glucocorticoid levels on brain structure rather than on any acute effects of high glucocorticoids (Sapolsky, 1987; Seckl and Olsson, 1995). Glucocorticoids readily diffuse into the brain from the circulation to activate high affinity mineralocorticoid receptors (MR) and lower affinity glucocorticoid receptors (GR). Both MR and GR are expressed in limbic regions involved in cognitive function (de Kloet et al, 1999; Oitzl and de Kloet, 1992). Tissue glucocorticoid levels are influenced, by 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), an intracellular glucocorticoid-amplifying
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