Glucocorticoid excess is associated with increased anxiety and accelerated cognitive decline. Concentrations of glucocorticoids within tissues, including the brain, are influenced by local metabolism. 5α-Reductase 1 (5αR1), expressed in brain, converts corticosterone to its A-ring reduced metabolites, which have a different spectrum of activities. Here, we investigated if mice homozygous for disrupted 5αR1 alleles (5αR1-KO) experience heightened anxiety and impaired learning and memory. Female, wild-type (WT) and 5αR1-KO littermates were housed singly (S) or in groups (G). At 6 months (young) and 1415 months (aged), anxiety (elevated plus maze and open field test; expressed as % time spent in most anxiogenic zones), and learning and memory (Y-maze and Morris Water-maze) were tested. Plasma corticosterone (0800 hrs) was quantified by ELISA. Data are mean±S.E.M. (KO-S vs KO-G vs WT-S vs WT-G), compared by two-way ANOVA,*P<0.05,**P<0.01 vs matched WT, n=17/group. Plasma corticosterone levels were not different between genotypes in young mice, or in aged mice when singly housed, but were lower in group-housed, aged, 5αR1-KO animals compared to WT (98±30* vs 245±69 nM). Genotype and housing had no effect on anxiety in young mice. However, aged 5αR1-KO mice were more anxious than WT when housed singly (EPM: 5.19±2.32** vs 11.30±1.83 vs 10.73±2.02 vs 10.83±3.13%). When young, 5αR1-KO mice were not cognitively impaired in either test of learning and memory. Aged 5αR1-KO mice were able to learn the Water-maze task, achieving the same performance as WT after 5 days of training. However, the rate at which they learned the task declined with age (P=0.05), independently of housing, whereas performance of WT mice did not change. We conclude that disruption of 5αR1 induces anxiety and adversely affects cognition with ageing; effects which are modified by environmental stress. Although systemic differences in metabolism or altered conversion of other steroids may play a role, these behavioral changes are consistent with glucocorticoid excess within the brain.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: British Heart Foundation.