Mineralocorticoid receptors guide spatial and stimulus-response learning in mice

Abstract

Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum-dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR-overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR-deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning.

Figure 1. Experimental design of training and memory testing.

Figure 2. Spatial task: latency to the exit hole over six training trials and spatial memory test.

A) Female MR-Tg mice (n = 19) take less time to find the exit hole than controls (n = 20). B) Female MR^CaMKCre mice take more time to find the exit hole than controls (n = 12 per group). C) Male MR^CaMKCre and control mice (n = 12 per group) have comparable latencies to locate the exit hole. Bars show mean ± SEM. *p<0.05 over trials, vs. control littermates. n.s. = not significant.

Figure 3. Stimulus-response (S-R) task: latency to the exit hole over six training trials on two days.

A) Female MR-Tg mice and controls have short and similar latencies to the exit hole. B) Female MR^CaMKCre mice take more time to locate the exit than controls in trials 3 and 5 on day 1, and in all trials on day 2. C) Male MR^CaMKCre mice take more time to locate the exit than controls on day 2. Bars show mean ± SEM. *p<0.05 vs. control littermates.