Corticosterone facilitates wbehavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone... Show moreCorticosterone facilitates wbehavioral 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 (MRCaMKCre) and their wild type littermates (MRflox/flox mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MRflox/flox mice and neither did the acute stressor. However, the MRCaMKCre mutants needed significantly more time to find the exit and made more hole visit errors than the MRflox/flox mice, especially when in proestrus and estrus. In addition, stressed MRCaMKCre mice in estrus had a shorter exit latency than the control estrus MRCaMKCre mice. About 70% of the female MRCaMKCre and MRflox/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 MRCaMKCre 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. Show less
Horst, J.P.; Carobrez, A.P.; Mark, M.H. van der; Kloet, E.R. de; Oitzl, M.S. 2012
Previous studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain-specific deletion of the MR gene ... Show morePrevious studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain-specific deletion of the MR gene (MRCaMKCre) were unable to show extinction of contextual fear, and could not discriminate between cue and context fear unlike control mice. In the present study, male and female (MRCaMKCre) mice and control littermates were used to study sex-specific fear conditioning, memory performance and extinction. The fear conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. We observed that at the end of the conditioning all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MRCaMKCre mice remembered and feared the context more than the control mice. Furthermore, female MRCaMKCre mice were not able to extinguish this memory even on the second day of memory testing. The female mutants also could not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MRCaMKCre mice and the controls showed extinction and were capable to discriminate, although the MRCaMKCre mice needed more time before they started extinction. These findings further support the relevance of MR for behavioral flexibility and extinction of fear-motivated behavior. In conclusion, the loss of MR in the forebrain results in large differences in emotional and cognitive behaviors between female and male mice, which suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders. Show less
Horst, J.P. ter; Mark, M.H. van der; Arp, M.; Berger, S.; Kloet, E.R. de; Oitzl, M.S. 2012
Corticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the... Show moreCorticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the consolidation of memory, the mineralocorticoid receptor (MR) mediates appraisal and initial responses to novelty. Recent findings in humans and mice suggest that under stress, the MR might be involved in the use of different learning strategies. Here, we used male mice lacking the MR in the forebrain (MRCaMKCre), which were subjected to 5-10 min acute restraint stress, followed 30 min later by training trials on the circular hole board. Mice had to locate an exit hole using extra- and intra-maze cues. We assessed performance and the use of spatial and stimulus-response strategies. Non-stressed MRCaMKCre mice showed delayed learning as compared to control littermates. Prior stress impaired performance in controls, but did not further deteriorate learning in MRCamKCre mice. When stressed, 20-30% of both MRCaMKCre and control mice switched from a spatial to a stimulus-response strategy, which rescued performance in MRCaMKCre mice. Furthermore, MRCaMKCre mice showed increased GR mRNA expression in all CA areas of the hippocampus and an altered basal and stress-induced corticosterone secretion, which supports their role in the modulation of neuroendocrine activity. In conclusion, our data provide evidence for the critical role of MR in the fast formation of spatial memory. In the absence of forebrain MR spatial learning performance was under basal circumstances impaired, while after stress further deterioration of performance was rescued by switching behavior increasingly to a stimulus-response strategy. (C) 2012 Elsevier Inc. All rights reserved. Show less
