Spatial learning of female mice: a role of the mineralocorticoid receptor during stress and the estrous cycle

Judith P. ter Horst, Jiska Kentrop, Marit Arp, Chantal J. Hubens, E. Ron de Kloet, Melly S. Oitzl

Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MR(CaMKCre)) and their wild type littermates (MR(flox/flox) mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MR(flox/flox) mice and neither did the acute stressor. However, the MR(CaMKCre) mutants needed significantly more time to find the exit and made more hole visit errors than the MR(flox/flox) mice, especially when in proestrus and estrus. In addition, stressed MR(CaMKCre) mice in estrus had a shorter exit latency than the control estrus MR(CaMKCre) mice. About 70% of the female MR(CaMKCre) and MR(flox/flox) mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MR(CaMKCre) mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones.