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Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

Lookup NU author(s): Professor Brian WalkerORCiD

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Abstract

© 2014 Elsevier Ltd. All rights reserved.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.

Publication metadata

Author(s): Wheelan N, Webster SP, Kenyon CJ, Caughey S, Walker BR, Holmes MC, Seckl JR, Yau JLW

Publication type: Article

Publication status: Published

Journal: Neuropharmacology

Year: 2015

Volume: 91

Pages: 71-76

Print publication date: 01/04/2015

Online publication date: 11/12/2014

Acceptance date: 02/12/2014

ISSN (print): 0028-3908

ISSN (electronic): 1873-7064

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.neuropharm.2014.12.005

DOI: 10.1016/j.neuropharm.2014.12.005

PubMed id: 25497454

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