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

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.

Keywords: Corticosterone; Fear conditioning; Hippocampus; Spatial memory; Y-maze.

Fig. 1

Experimental schedule for the effects of UE2316 treatment on spatial and contextual fear memory in a vehicle controlled cross over design. Prior to behavioural testing (Y-maze (2 h inter-trial interval (ITI)) and fear conditioning (FC)), 24 m aged mice were treated via subcutaneously implanted Alzet osmotic minipumps with UE2316 (10 mg/kg/day) or vehicle (n = 8–9/group).

Fig. 2

UE2316 reduces 11β-HSD1 activity in the aged mouse brain. 11β-HSD1 activity measured ex-vivo as % conversion of [³H]-11dehydrocorticosterone to [³H]-corticosterone in hippocampus and cortex from UE2316 and vehicle treated aged mice. Results represent mean ± SEM. ***P < 0.001 vs vehicle group.

Fig. 3

Short-term UE2316 treatment reversibly improves spatial memory in aged C57BL/6J mice. (A) All aged mice were tested in the immediate version of the Y-maze (1 min inter-trial interval (ITI)) confirming preferential exploration of the novel arm and no visual problems identifying cues around the maze. (B) UE2316 improved spatial memory (more time spent in novel arm) on the 10th day of treatment while vehicle treated aged mice remained impaired in the Y-maze (n = 8–9/group). (C) Improved spatial memory in UE2316 treated mice reversed after swapping to vehicle, while impaired spatial memory in vehicle-treated mice improved after swapping to UE2316. Results represent mean ± SEM. ***P < 0.0001, §P < 0.01 and ♯P < 0.05 vs. other arms. *P < 0.05 vs corresponding treatment.

Fig. 4

Short-term UE2316 treatment impairs contextual fear memory in aged C57BL/6J mice with effects persisting after drug withdrawal. (A) When exposed to training in context A, no freezing was observed prior to foot shocks but after each foot shock, all mice showed moderate levels of freezing which were not affected by UE2316 treatment. (B) UE2316 treatment reduced contextual fear memory retention compared to vehicle controls for each consecutive day following training. Level of freezing declined with each consecutive day of re-exposure to context A. (C) When treatments were swapped over mice now showed low levels of freezing when exposed to training context B, even prior to the foot shocks. UE2316 did not affect the level of freezing after each foot shock. (D) UE2316 (previously vehicle) treatment now enhanced contextual fear memory retention 1 day following training. Level of freezing declined with each consecutive day of re-exposure to context B. Results represent mean ± SEM. ***P < 0.001, **P < 0.01, *P < 0.05 vs corresponding treatment group.