Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour

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Summary

An imbalance between central glucocorticoid (GR) and mineralocorticoid (MR) receptors is proposed to underlie the HPA axis dysregulation that associates with susceptibility to psychopathology (anxiety, PTSD). To test this ‘balance hypothesis’ we examined whether the impact of MR levels upon HPA-axis control and behaviour depended on the relative levels of GR and vice versa. Avoiding antenatal maternal ‘programming’ effects by using littermates, we generated mice with forebrain MR over-expression (MRhi) and/or simultaneous global GR under-expression (GRlo). We found a significant interaction between MR and GR in control of the HPA-axis under stressed but not basal conditions. With reduced GR levels, HPA-axis activity in response to restraint stress was enhanced, likely due to impaired negative feedback. However, high MR in concert with reduced GR minimised this HPA-axis overshoot in response to stress. MR:GR balance also played a role in determining strategies of spatial memory during a watermaze probe trial: when coupled with GR under-expression, MRhi show enhanced perseveration, suggesting enhanced spatial recall or reduced exploratory flexibility. Other alterations in cognitive functions were specific to a single receptor without interaction, with both MRhi and GRlo manipulations independently impairing reversal learning in spatial and fear memory tasks. Thus, MR and GR interact in specific domains of neuroendocrine and cognitive control, but for other limbic-associated behaviours each receptor mediates its own repertoire of responses. Since modulation of HPA-axis and behavioural dysfunction associated with high levels of MR, selective ligands or transcriptional regulators may afford novel therapeutic approaches to affective psychopathologies.

Introduction

An imbalance between central corticosteroid receptors is proposed to underlie dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and vulnerability to stress-related psychiatric disorders (e.g. anxiety, depression, post traumatic stress disorder [PTSD]) (e.g. De Kloet, 1991, Sapolsky, 2000).

In the brain, glucocorticoids act through two receptors: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Both belong to the same family of intracellular ligand-dependent transcription factors. Though highly homologous, particularly in the DNA binding domain, there is limited overlap in the sets of target genes they regulate (Datson et al., 2001). The receptors are also found in the cell membrane where they exert fast, non-genomic effects on neuronal excitability (Joels et al., 2009, Karst et al., 2005). MR and GR are abundant in the limbic system (e.g. hippocampus, amygdala), circuitry essential for emotion, cognition and HPA axis control (Ahima and Harlan, 1990). MR and GR mediate the initiation (possibly via membrane MR; Karst et al., 2005) and termination of the HPA axis stress response (primarily via negative feedback at intracellular GR, but also MR) and modulate acquisition, processing, storage and retrieval of stressful experiences (e.g. Oitzl et al., 2001, Sapolsky et al., 2000). Imbalance between MR and GR-mediated actions in limbic system neurons may lead to an exaggerated or inadequate initial HPA axis response to stress, impaired containment, delayed recovery and compromised adaptation. Crucially, such changes are hypothesised to increase vulnerability to affective disease (De Kloet et al., 1998).

Polymorphisms in genes encoding MR and GR associate with altered HPA axis function and depression, suggesting a causal role (van West et al., 2006, Wust et al., 2008). In mice, global reduction in GR signalling activates the HPA axis and impairs cognition (Oitzl et al., 2001, Ridder et al., 2005), while forebrain-selective deletion of GR increases corticosterone levels, reduces anxiety and increases depressive-like behaviour (Boyle et al., 2005, Tronche et al., 1999). In contrast, forebrain-specific deletion of MR impairs learning and memory (Berger et al., 2006), whereas forebrain over-expression of MR enhances memory and reduces anxiety (Lai et al., 2007, Rozeboom et al., 2007).

Experiments that change the level of only one receptor fail to reveal if the observed effects are a consequence of the absolute level of the altered receptor, or the resulting imbalance between MR and GR. Here, to address the ‘balance’ hypothesis directly, we crossed mice underexpressing GR globally (modelling human GR haploinsufficiency) with mice over-expressing MR in the forebrain (avoiding changes in kidney that can alter salt balance and blood pressure). Importantly, these experiments were all carried out on mouse littermates (with each genetically identical dam bearing all genotypes), removing the confounding effects of developmental programming by the in utero and early postnatal environment which otherwise potently impact on HPA axis and affective functions (e.g. Harris and Seckl, 2011).

Section snippets

Generation of mice

Mice were generated by crossing male mice heterozygous for a null allele of GR, which have half the normal density of GR in brain (GRbgeo/+, here termed GRlo mice) (Michailidou et al., 2008), with female mice over-expressing human MR in the forebrain under the control of the CamKIIa promoter (MRtg/+, here termed MRhi mice) (Lai et al., 2007), ensuring identical maternal environment for all experimental mice. Both parent strains were back-crossed to the C57BL/6J background >16 generations and

Alteration of MR or GR does not affect expression of the other

MRhi mice had ∼3.2-fold higher level of MR mRNA expression (F1,14 = 251.8, P < 0.0001) and GRlo mice had ∼50% reduced GR mRNA levels in the hippocampus (F1,14 = 33.4, P < 0.0001; Table 1). MRhi mice also had an ∼8.5-fold increase in MR mRNA expression levels in the basolateral amygdala (BLA) (F1,16 = 355.1, P < 0.0001; Table 1) and GRlo mice had ∼37% reduced GR mRNA levels in the BLA (F1,15 = 9.2, P = 0.0085). Crucially, under-expression of GR (either alone or in concert with MRhi) did not alter co-localised

Discussion

Our data illustrate the exquisite complexity of the stress system and emphasise the importance of context upon the behavioural and cognitive effects of altered MR:GR balance. MR and GR interact to control the HPA axis in response to restraint stress, notably when GR is low. Importantly, in the limbic-associated cognitive behaviours, altered levels of both GR and MR had independent and interactive consequences for the strategy used to reverse a learned spatial memory. Crucially, the failure to

Role of the funding sources

This work was supported by a European Science Foundation (EuroSTRESS) grant to APH, JRS and ERK.

Conflict of interest

E.R. de Kloet is an advisor to Dynacorts Therapeutics and Corcept Therapeutics, though he has no commercial interest in the material presented in this manuscript. All other authors declare that they have no conflicts of interest.

Acknowledgements

This work was supported by a European Science Foundation (EuroSTRESS) grant to APH, JRS and ERK. We would like to thank three anonymous reviewers for their constructive comments on the manuscript.

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