Brain Mineralocorticoid Receptor Research Articles

Brain mineralocorticoid receptor in health and disease: From molecular signalling to cognitive and emotional function.

Brain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, as well as the effects of aldosterone itself in relation to salt homeostasis. Brain stem MRs respond to aldosterone, whereas forebrain MRs mediate rapid and delayed glucocorticoid effects in conjunction with the glucocorticoid receptor (GR). MR‐mediated effects depend on age, gender, genetic variations, and environmental influences. Disturbed MR activity through chronic stress, certain (endocrine) diseases or during glucocorticoid therapy can cause deleterious effects on affective state, cognitive and behavioural function in susceptible individuals. Considering the important role MR plays in cognition and emotional function in health and disease, MR modulation by pharmacological intervention could relieve stress‐ and endocrine‐related symptoms. Here, we discuss recent pharmacological interventions in the clinic and genetic developments in the molecular underpinnings of MR signalling. Further understanding of MR‐dependent pathways may help to improve psychiatric symptoms in a diversity of settings.LINKED ARTICLESThis article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others’ emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD.

Identification of mineralocorticoid receptor target genes in the mouse hippocampus

Brain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respond to the same glucocorticoid hormones but can have differential effects on cellular function. Several lines of evidence suggest that MR‐specific target genes must exist and might underlie the distinct effects of the receptors. The present study aimed to identify MR‐specific target genes in the hippocampus, a brain region where MR and GR are co‐localised and play a role in the stress response. Using genome‐wide binding of both receptor types, we previously identified MR‐specific, MR‐GR overlapping and GR‐specific putative target genes. We now report altered gene expression levels of such genes in the hippocampus of forebrain MR knockout (fbMRKO) mice, killed at the time of their endogenous corticosterone peak. Of those genes associated with MR‐specific binding, the most robust effect was a 50% reduction in Jun dimerization protein 2 (Jdp2) mRNA levels in fbMRKO mice. Down‐regulation was also observed for the MR‐specific Nitric oxide synthase 1 adaptor protein (Nos1ap) and Suv3 like RNA helicase (Supv3 l1). Interestingly, the classical glucocorticoid target gene FK506 binding protein 5 (Fkbp5), which is associated with MR and GR chromatin binding, was expressed at substantially lower levels in fbMRKO mice. Subsequently, hippocampal Jdp2 was confirmed to be up‐regulated in a restraint stress model, posing Jdp2 as a bona fide MR target that is also responsive in an acute stress condition. Thus, we show that MR‐selective DNA binding can reveal functional regulation of genes and further identify distinct MR‐specific effector pathways.

Cortisol modulates the engagement of multiple memory systems: Exploration of a common NR3C2 polymorphism

Exposure to acute stress has been shown to result in a shift from declarative toward non-declarative learning, presumably mediated by brain mineralocorticoid receptors (MRs). In this study, we aimed to replicate and extend these findings by investigating the role of stress-associated cortisol secretion on learning behavior. Furthermore, we explored the influence of a well-characterized common single nucleotide polymorphism of the MR gene (rs2070951; minor allele frequency: 49.3%) previously shown to influence MR expression and HPA axis activity. Healthy males (n = 74) were exposed to the Trier Social Stress Test or a control condition prior to performing a probabilistic classification task (Weather Prediction Task). The use of a non-declarative learning strategy continuously increased over the course of the learning task after stress exposure, but leveled in the control condition. The shift toward a non-declarative strategy in the stress group was associated with better learning performance. Higher pre-stress cortisol levels favored the adoption of a non-declarative learning strategy. rs2070951 C/C-carriers in contrast to G-allele carriers exhibited a larger secretion of cortisol under stress. Furthermore, control participants homozygous for the C-allele adopted a non-declarative learning strategy less often than stressed participants, whereas the choice of strategy was independent of stress in G-allele carriers. The failure to switch strategies resulted in poorer performance, suggesting a beneficial effect of stress in dependence of MR variation. Consistent with previous findings, the results provide further support for cortisol as a driving force in coordinating the competition between multiple memory systems under stress.

Brain Mineralocorticoid Receptors and Resilience to Stress.

Exposure to stressful experiences triggers the release of-among others-glucocorticoids from the adrenal glands. These hormones, cortisol and corticosterone in humans and rodents respectively, activate mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) that regulate neuronal activity and behavioral adaptation to stressful experiences. This review discusses molecular properties of MRs, the role of MRs in regulating neuronal function and behavior and, ultimately, evidence that enhanced MR function may confer resilience to stressful experiences.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes.

In 1968, Bruce McEwen discovered that 3H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era dominated by the conundrum of two types of corticosterone-binding receptors in the brain, which led to the identification of the high-affinity corticosterone receptor as the 'promiscuous' MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the function of the brain MR from that of the closely related GR on different levels of biological complexity. Finally, the synthesis section that highlights the two faces of brain MR: Salt and Stress. 'Salt' refers to the regulation of salt appetite, and reciprocal arousal, motivation and reward, by a network of aldosterone-selective MR-expressing neurons projecting from nucleus tractus solitarii (NTS) and circumventricular organs. 'Stress' is about the limbic-forebrain nuclear and membrane MRs, which act as a switch in the selection of the best response to cope with a stressor. For this purpose, activation of the limbic MR promotes selective attention, memory retrieval and the appraisal process, while driving emotional expressions of fear and aggression. Subsequently, rising glucocorticoid concentrations activate GRs in limbic-forebrain circuitry underlying executive functions and memory storage, which contribute in balance with MR-mediated actions to homeostasis, excitability and behavioural adaptation.

Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus.

Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND) 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg) mice. Low-stress contextual (i.e., object relocation) memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear) memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.

A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy.

Some serious medical conditions require life-saving treatment with high doses of synthetic glucocorticoids such as dexamethasone. A substantial number of patients subjected to this treatment develops psychosis, mood disturbances, or sleep problems. A recent clinical trial demonstrated that dexamethasone therapy for young patients with acute lymphoblastic leukemia caused severe adverse psychological effects and sleep disturbances in about 30% of these patients. These side effects were ameliorated by coadministration of a low dose of the naturally occurring glucocorticoid hormone cortisol. This paradoxical finding was predicted by the idea that the synthetic glucocorticoid targets the glucocorticoid receptor, causing suppression of cortisol secretion and, thus, depletion of the brain mineralocorticoid receptor (MR) of its endogenous ligand. The refill of the unoccupied brain MR with physiological amounts of cortisol ameliorates the dexamethasone-induced psychological side effects. In the present report, we discuss the mechanistic underpinning of the MR refill concept in glucocorticoid therapy.

Natriuretic peptides regulate sympathetic nervous activity independent of mineralocorticoid receptor

Background Natriuretic peptides (ANP/BNP) increase cGMP and exert cardiovascular protective effects via guanylyl cyclase A (GC-A) receptor, which is distributed in many organs such as the heart, the vasculature and the brain [1]. Sympathetic nervous system (SNS) as well as reninangiotensin-aldosterone-system contributes to cardiovascular disease. However, the endogenous effect of GC-A signaling on SNS is not investigated. Recent study shows that activated mineralocorticoid receptor (MR) in the hypothalamus induces systemic SNS activation [2], whereas ANP infusion in human inhibited SNS activity in the heart [3]. Notably, it is reported that ANP counteracts the deleterious effects of MR in the heart [4]. Therefore, we hypothesized that ANP suppresses MR activation in the brain and leads to the inhibition of SNS activity. Purpose To investigate whether ANP/GC-A signaling inhibits SNS activity through the suppression of the brain MR, we examined urinary catecholamine secretion in global GC-A receptor KO mice and the effect of intracerebroventricular (ICV) infusion of MR blocker. Methods and results We measured blood pressure (BP) and urinary norepinephrine (U-NE) secretion in wild type and global GC-A KO mice. Both BP and U-NE is significantly higher in GC-A KO than in wild type mice, indicating SNS is activated in GC-A KO mice. To study whether SNS activation is caused by the brain MR, we infused Eplerenone (MR blocker) into the ICV with osmotic mini pump for 2 weeks. Contrary to our hypothesis, both BP and U-NE did not change after 2 weeks ICV infusion, suggesting that activated SNS in GC-A KO is independent of MR. Furthermore, high sodium diet (NaCl 6%) for 2 weeks did not increase BP and U-NE in GC-A KO mice. MR protein expression in the hypothalamus was almost similar between GC-A KO and Wild type mice. These data suggest that SNS activity in GC-A KO mice is independent of MR and insensitive to sodium load. Unexpectedly, the most of GC-A KO mice died after ICV infusion of Losartan (AT1 receptor blocker), whereas wild type mice survived. Conclusion Natriuretic peptides/GC-A signaling regulates SNS activity independent of both brain MR and sodium load. Brain AT1 receptor might be important in the regulation of cardiovascular system in global GC-A KO mice.

Brain mineralocorticoid receptor: The other one

For many years the glucocorticoid receptor – mediating slow genomic actions – was considered to be the stress receptor in the brain, since intracellular mineralocorticoid receptors (MRs) are already considerably occupied under rest and thus not available for corticosteroids. A decade ago it was discovered that pyramidal cells e.g. in the hippocampus and basolateral amygdala also respond quickly to corticosterone, via nongenomically acting MRs that require a tenfold higher concentration than MRs acting through genomic signaling. Subsequent behavioral studies in humans and rodents have shown that these rapid MR-mediated actions are important for an appropriate quick response to a stressful condition. It is now thought that directly after stress onset MRs mediate a shift in resources towards striatal regions, at the cost of the hippocampus and prefrontal cortex. Behaviorally this is reflected in heightened attention and reverting to the use of more simple strategies e.g. in spatial or fear learning. This is highly adequate in the given situation: blockade of MRs impairs overall behavioral performance. Also in the face of prolonged adversity (chronic unpredictable stress) or stress during critical developmental windows (fragmented maternal care during the first postnatal week) do MRs exert beneficial effects, since forebrain-specific MR overexpression can rescue behavioral impairment seen after such conditions in wildtype animals. The brain MR is therefore not only essential for an appropriate neuronal and behavioral response during acute stress conditions but also beneficial in more severe stress conditions that are known to be a risk factor for psychopathology in humans.

Behavioral stress induces regionally-distinct shifts of brain mineralocorticoid and glucocorticoid receptor levels

Mineralocorticoid and glucocorticoid receptors (MRs and GRs) mediate the impact of stress on brain function primarily by affecting gene transcription in the cell nucleus. In vitro studies using hippocampal neurons indicate that MRs and GRs translocate to the nucleus after binding to the stress hormone corticosterone, yet the in vivo temporal dynamics of MR and GR levels in other limbic regions critical for the stress response, however, are largely unknown. Rats underwent an elevated platform (EP) stress procedure and brain tissue was sampled from the amygdala (AMY), medial prefrontal cortex (mPFC), dorsal hippocampus and ventral hippocampus. By measuring MR and GR levels in the nuclear fraction from the tissue sampled, we observed striking shifts in the protein levels that varied by receptor, brain region and by the time after EP stress. These findings indicate that the subcellular trafficking of corticosteroid receptors display distinct temporal dynamics in different limbic regions after behavioral stress. These heterogeneous effects could underlie contrasting regional responses to stress within the brain, and they highlight the importance for systems-level analysis of stress responsivity.

Abstract 441: Aldosterone-salt Hypertension Depends on the SFO, Central Aldosterone Synthase and MR Specifically in the PVN

Central blockade of mineralocorticoid receptor (MR) prevents aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats with telemetry probes were treated with chronic intra-cerebroventricular infusion of aldo synthase (AS) inhibitor FAD286 (25 μg/day), MR blocker eplerenone (5 μg/day) or vehicle. After 2 days, subcutaneous (sc) aldo infusion (1 μg/h) was started and saline was provided as drinking water. In a second set of rats with telemetry, electrolytic or sham lesions of the SFO, or bilateral intra-PVN infusion of AAV-MR-siRNA or AAV-SCM-siRNA (1 μl of 5x10 10 genomic particles/ml) at 100ng/min were performed, and sc aldo infusion started 1 week later. AAV-MR-siRNA decreased MR mRNA and protein expression in the PVN by ~60 and 30%, but had no effects on MR expression in other nuclei such as the SFO and SON. SFO lesion, blockade of brain AS or MR, or knockdown of MR in the PVN attenuated aldo-salt hypertension by ~60%. Data=means± SE (n=5-9/group). *p<0.05, vs. others, a:p<0.05, vs. vehicle or sham lesion. These results suggest that an increase in circulating aldosterone may via MR and AT 1 R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR in the PVN activate a central aldosterone-MR-AT 1 R neuro-modulatory pathway, which plays a major role in the progressive hypertension. (Supported by grant # FRN:MOP-74432 from the Canadian Institutes of Health Research)

Mineralocorticoid receptor blockade during a rat’s first violent encounter inhibits its subsequent propensity for violence.

In individuals naïve to serious conflict in an unfamiliar environment, violence has long-lasting effects on subsequent aggressive behavior. This effect of the stressful experience of a first violent conflict occurs in victims as well as offenders. The authors study in the male rat as offender the role of a rapid corticosterone signal mediated by brain mineralocorticoid receptors (MR) in adjusting the threshold of aggressive responses. For this purpose, the authors have applied electrical stimulation of the brain's aggression circuit via the hypothalamic attack area or HAA. Using this paradigm, they found that in inexperienced rats, retesting of the animals on subsequent days facilitated aggression. Hypothalamic attack thresholds decreased to about 50% of their initial level. However, blocking the MR once with the mineralocorticoid antagonist spironolactone, during the very first evoked attacks, permanently prevented attack facilitation in subsequent conflicts in that same environment. The MR-mediated effect blocked by the antagonist occurred within an hour following the start of the first aggression tests only. A later MR blockade was not effective. These findings suggest that the corticosterone stress response during a very first serious conflict initializes an enhanced propensity for violent aggression through the brain MR.

88 BRAIN MINERALOCORTICOID RECEPTOR ACTIVATION MEDIATES ARTERIAL PRESSURE ELEVATION THROUGH BRAIN OXIDATIVE STRESS-INDUCED SYMPATHOEXCITATION IN SALT-SENSITIVE AND OBESITY-INDUCED HYPERTENSION

Objectives and Background: We have shown previously that sympathoexcitation by brain oxidative stress mediates arterial pressure (AP) elevation in salt-sensitive and obesity-induced hypertension. Sympathoexcitatory roles of brain mineralocorticoid receptor (MR) have been documented, but the detailed mechanisms have not been fully elucidated. We have also shown that MR activation could mediate oxidative stress-induced cardiac and renal dysfunction. Then, we hypothesized that brain MR activation could mediate AP elevation through brain oxidative stress-induced sympathoexcitation. Design and methods: We used high-salt (8%)-loaded Dahl-salt-sensitive rats (Dahl-S) as the salt-sensitive hypertension model, and high-fat (45% kcal as fat)-fed Sprague-Dawley rats as the obesity-induced hypertension model. Sgk-1 and PAI-1 mRNA expression in the isolated hypothalamus was evaluated by real-time quantitative RT-PCR. We examined effects of chronic intracerebroventricular eplerenone on sympathetic nerve activity (response to hexamethonium and urinary norepinephrine) and AP. In Dahl-S, we evaluated the responses of renal sympathetic nerve activity (RSNA) and AP to acute intracerebroventricular administration of tempol, and the hypothalamic oxidative stress level. Results: Salt loading in Dahl-S and fat loading in Sprague-Dawley rats significantly enhanced mRNA expression of Sgk-1 and PAI-1 in the hypothalamus. Intracerebroventricular eplerenone significantly reduced sympathetic nerve activity and AP both in salt-loaded Dahl-S and high-fat-fed rats. Reductions in RSNA and AP values elicited by acute intracerebroventricular tempol, and hypothalamic oxidative stress level were significantly suppressed in intracerebroventricular eplerenone-treated salt-loaded Dahl-S compared with vehicle-treated group. Conclusions: Brain MR activation can be a possible common pathogenic background of AP elevation through brain oxidative stress-induced sympathoexcitation in salt-sensitive and obesity-induced hypertension.

Enhanced aldosterone synthesis and insufficient activation of cyp2c9‐EET pathway in the brain play a pivotal role in salt‐induced sympathetic activation in mice with pressure overload

BackgroundRecently, we demonstrated that high‐salt (HS) intake augments sympathetic drive via brain mineralocorticoid receptor (MR) – epithelial Na channels (ENaCs) pathway activation in mice with pressure‐overload (PO‐mice). In the present study, we determined whether imbalance between aldosterone synthesis and activation of cyp2c9‐EET plays a pivotal role in sympathetic activation in this model.Methods and ResultsWe performed aortic banding to create PO‐mice. Sham operation was performed as control (Sham‐mice). Four weeks after aortic banding, mice were fed with either a HS (8%) diet or a regular‐salt diet for additional 4 weeks. Urinary norepinephrine excretion, a marker of sympathetic activity was significantly increased by HS in PO‐mice, but not in Sham‐mice. The expressions of brain MR and the ratio of phosphorylated/total serum glucocorticoid inducible kinase‐1(sgk‐1), a marker of MR activity increased in PO‐mice. Furthermore, unlike in Sham‐mice, PO‐induced MR activation maintained despite HS loading. Intracerebroventricular (ICV) infusion of aldosterone synthesis inhibitor, FAD 286A (100 μg/kg/day, 4 weeks), decreased brain MR activity with the reduction of sympathetic drive. We also examined the cyp2C9 expression and 11,12‐epoxyeicosatrienoic acids (EET) concentration in the brain, a major pathway to inhibit ENaCs. HS increased cyp2c9 expression and 11,12‐EET concentration in the brain only in Sham‐mice, but not in PO‐mice.ConclusionIn PO‐mice, HS increases sympathetic drive via the activation of brain MR‐ENaCs pathway through aldosterone‐dependent MR activation and insufficient activation of cyp2c9‐EET pathway.

Aldosterone Acts in the Nucleus of the Solitary Tract to Alter Stress Responsiveness

Aldosterone (aldo) acts at brain mineralocorticoid receptors (MR) to increase arterial pressure. We hypothesized that activation of MR selectively within the Nucleus Tractus Solitarius (NTS), a key circulatory control center, would enhance the cardiovascular response restraint stress. Mean arterial pressure (MAP) was measured by radiotelemetry in adult male Sprague–Dawley rats. Chronic elevations in aldo levels within the NTS were achieved by implanting pellets of 1% aldo over the NTS (n=4). Sham pellets were made of silastic (n=4). All rats were subjected to 60 min of restraint stress daily for 11 days. On day 12 they were exposed to a novel stress by placing them in 1 cm of room temp water for 15 min. Aldo did not alter baseline MAP. Aldo attenuated the integrated MAP response to restraint stress on the first day (990±50 mmHg/60 min vs 1510± 82 mmHg/60 min, aldo vs sham, P=0.002). The MAP response to the final restraint stress was not significantly affected by aldo. With water stress, the integrated MAP response was enhanced in the aldo‐ vs. the sham‐treated rats (416±14 mmHg/15 min vs. 332±32 mmHg/15 min, P=0.054). Compared with the sham rats, the aldo‐treated rats gained less weight during the period of chronic stress (2±5 gm, n=4 vs. 24±7 gm, n=3, P=0.04). We conclude that aldosterone acts in the NTS to influence stress responsiveness. Support: NIH#HL 076807, AHA#GRNT 4460047.

Predator stress-induced persistent emotional arousal is associated with alterations of plasma corticosterone and hippocampal steroid receptors in rat

To investigate the long-term effects of psychological stress on emotionality, the emotional arousal of rats in 4 months after predator stress was assessed in both an open field environment and elevated plus maze. We also assessed the levels of plasma corticosterone (CORT) by radioimmunoassay, the distributions of brain glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) by immunohistochemistry, and the expressions of GR and MR by Western blot. The results showed that intense predator stress, which was adjusted to ensure consistent stressor intensity using rat tonic immobility behavior, successfully induced lasting decreased locomotor activity and habituation to novel environments, suppressed exploratory behavior, and increased anxiety-like behavior. The plasma CORT levels dramatically increased 1h after stress, then returned to basal levels at 1wk, decreased 1 month later, and remained significantly lower than control levels 4 months after exposure to stress. Immunohistochemical analysis showed that GR was markedly increased in the hippocampus and frontal cortexes of stressed rats and that the changes in the hippocampus were more pronounced. In contrast, MR expression was significantly decreased in both brain regions. Western analysis confirmed these dramatically elevated levels of GR expression and lower levels of MR expression in the hippocampus 4 months after stress. We conclude that acute severe psychological stress may induce long-term emotional behavioral changes, and that different patterns in plasma CORT, alterations in brain corticoid receptors, and increased hippocampal vulnerability to the effects of predator stress may play important roles in the persistent emotional arousal induced by intense psychological stress.

Role of mineralocorticoid action in the brain in salt‐sensitive hypertension

1. The mechanisms by which excessive salt causes hypertension involve more than retention of sodium and water by the kidneys and are far from clear. Mineralocorticoids act centrally to increase salt appetite, sympathetic drive and vasopressin release, resulting in hypertension that is prevented by the central infusion of mineralocorticoid receptor (MR) antagonists. The MR has similar affinity for aldosterone and the glucocorticoids corticosterone or cortisol. Specificity is conferred in transport epithelia by the colocalization of the MR with 11β-hydroxysteroid dehydrogenase Type 2. Coexpression also occurs in some neurons, notably those of the nucleus tractus solitarius that are activated by sodium depletion and aldosterone and mediate salt-seeking behaviour. 2. The salt-induced hypertension of the Dahl salt-sensitive rat is mitigated by the central infusion of a mineralocorticoid antagonist even though circulating aldosterone is normal or reduced in salt-sensitive (SS). Contrary to reports that salt appetite in the Dahl salt-sensitive rat is depressed, we found that it is increased compared with that in Spraque-Dawley rats. 3. Extra-adrenal aldosterone synthesis in the brain occurs in minute amounts that could only be relevant locally. Expression of aldosterone synthase mRNA and aldosterone concentrations in the brain of Dahl salt-sensitive rats are increased compared with Spraque-Dawley rats. The central infusion of inhibitors of aldosterone synthesis lowers salt-induced hypertension in the Dahl salt-sensitive rat, suggesting a role for excessive Dahl salt-sensitive synthesis in the brain. Brain MR, particularly those in the paraventricular nuclei, regulate inflammatory processes that are exacerbated by sodium and lead to cardiovascular dysfunction.

NUCLEAR RECEPTORS

NUCLEAR RECEPTORS

A Role for Mineralocorticoid Receptors in the Physiology of the Ovine Fetus: Effects on ACTH and Lung Liquid Composition

In the human and ovine fetus, the presence of 11β-hydroxysteroid dehydrogenase 1 allows cortisol and other corticosteroids to act at mineralocorticoid receptors (MRs) in lung and brain. To test the physiologic role of MRs in the late gestation fetus, fetal lambs were infused with a specific MR antagonist for 12 h. Infusion of the MR antagonist significantly increased plasma ACTH and cortisol concentrations. Infusion of the MR antagonist also significantly increased fetal Pco2 and hematocrit, and decreased fetal pH, but did not alter fetal heart rate or blood pressure. Infusion of the MR antagonist altered the ratio of Na⁺ to K⁺ in lung fluid but did not alter the rate of production of lung liquid or the expression of the epithelial sodium channel α or of the Na,K ATPaseα1 in lung. These results suggest that corticosteroids act at MR to regulate ACTH and blood volume and modulate lung fluid composition in the fetus, but basal levels of corticosteroids do not alter lung liquid production rate through effects on MR.