Endocrine Abstracts (2012) 28 P305

Ageing and social isolation increase susceptibility to anxiety in mice lacking 5[alpha]-reductase type 1

Emma Di Rollo, Dawn Livingstone, Brian Walker & Ruth Andrew

University/BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.

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 14–15 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.

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