IntechOpen

Home > Books > Aldosterone-Mineralocorticoid Receptor - Cell Biology to Translational Medicine

Open access peer-reviewed chapter

MR/GR Signaling in the Brain during the Stress Response

Written By

Edo R. de Kloet and Onno C. Meijer

Submitted: 22 May 2019 Reviewed: 04 June 2019 Published: 25 September 2019

DOI: 10.5772/intechopen.87234

Aldosterone-Mineralocorticoid Receptor IntechOpen
Aldosterone-Mineralocorticoid Receptor Cell Biology to Translational Medicine Edited by Brian Harvey

From the Monograph

Aldosterone-Mineralocorticoid Receptor

Edited by Brian Harvey and Frederic Jaisser

Book Details Order Print

Chapter metrics overview

1,255 Chapter Downloads

View Full Metrics
Advertisement

Abstract

This contribution is about mineralocorticoid receptors (MRs) in their capacity as mediators of glucocorticoid action in the brain. This paradox has evolved because MRs are promiscuous and bind with high-affinity cortisol and corticosterone as well as aldosterone, deoxycorticosterone, and progesterone. The MRs “see,” however, predominantly glucocorticoids, because of their 100–1000-fold excess over aldosterone; bioavailability is further enhanced because of local regeneration of glucocorticoids by 11βOH-steroid dehydrogenase (HSD-1). In contrast to these glucocorticoid-preferring MR, the evolutionary later appearance of aldosterone-selective MR in epithelial cells depends on co-localization with the oxidase 11β-hydroxysteroid-dehydrogenase type 2 (HSD-2) in a few hundred neurons in the nucleus tractus solitarii (NTS), which innervate frontal brain regions to regulate cognitive, emotional, and motivational aspects of salt appetite. The glucocorticoid-MRs and classical glucocorticoid receptors (GRs) mediate in a complementary manner the glucocorticoid coordination of circadian events and mediate the regulation of stress coping and adaptation. If an individual is exposed to a threat, MRs are crucial for the selection of a particular coping style, which is via GR activation subsequently stored in the memory for future use. Our contribution is concluded with the notion that an imbalance in MR- and GR-mediated actions increases susceptibility to stress-related disorders.

Keywords

  • stress
  • brain
  • behavior
  • inflammation
  • glucocorticoid receptors
  • mineralocorticoid receptors

1. Introduction

The naturally occurring glucocorticoids, cortisol and corticosterone (the latter only in rodents), are secreted as end products of the hypothalamus-pituitary-adrenal (HPA) axis. The glucocorticoids have two modes of operation. Firstly, the hormones synchronize and coordinate circadian and sleep-related events. This action is based on hourly ultradian pulses with increasing amplitude toward the start of the active period with the goal to generate the necessary energy for the day to come. The hourly pulses maintain responsivity to the glucocorticoids. The frequency and amplitude of the glucocorticoid pulses may change as is the case during, e.g., inflammatory disorders and depression, or may become irregular as part of the aging process. High glucocorticoid concentrations prevent the onset of sleep [1, 2, 3].

Secondly, the glucocorticoids mediate the response to stress. A “stress reaction” can be due to physical stimuli such as pain, blood loss, and infection or can be psychogenic. Anticipation is an important component of the psychogenic stress reaction. Hence, the prediction of an upcoming event and the ability to exert control are essential for effective coping irrespective whether it concerns an adverse experience or a reward. Actually, stress is the “spice of life” and essential for adaptation and survival. However, the most severe stressor is characterized by inability to predict upcoming events and uncertainty during a threat. If uncertainty because of lack of control persists, the very same glucocorticoids that promote adaptation are now disruptive, facilitate breakdown of adaptation, reduce resilience, and enhance vulnerability to disease [4].

Glucocorticoid secretion from the adrenocortical zona fasciculata is under the control of pituitary adrenocorticotropic hormone (ACTH) that is cleaved from the large precursor molecule: pro-opiomelanocortin (POMC). The anterior pituitary synthesis of POMC is driven by corticotropin-releasing hormone (CRH) from neurosecretory cells of the paraventricular nucleus (PVN) in the hypothalamus; co-localized vasopressin amplifies the CRH-induced release of ACTH. Physical stressors directly activate CRH neurons via ascending neuronal projections of the brain stem. Psychological stressors are processed in higher brain regions for appraisal, decision-making, and choice of coping style to deal with the stressor. At last, the stress reaction dissipates and the experience is stored in the memory [5].

Advertisement

2. Corticosteroid receptors

The action of glucocorticoids is mediated by two types of corticosteroid receptors. One type is, surprisingly, the mineralocorticoid receptor (MR). This receptor was first identified in 1968 by Bruce McEwen: retention of 3H-labeled corticosterone was observed in hippocampal neurons at 1 hour after administration of the tracer to an adrenalectomized (ADX) rat [6]. 3H-aldosterone given to ADX animals showed essentially the same neuroanatomical distribution pattern as 3H-corticosterone. The MR was cloned: immunoreactive (ir) MR protein and MR gene expression showed the same distribution pattern as radioligand binding in the hippocampus [7, 8].

The GR was initially not detected by in vivo radioligand binding studies for two reasons. Firstly, the amount of radiolabeled corticosterone tracer was insufficient to occupy GR, because this receptor binds cortisol and corticosterone with a tenfold lower-affinity than the high-affinity MR. Second, our in vivo tracer studies with the high-affinity GR ligand, dexamethasone, did not provide a signal in the brain because the synthetic steroid was exported by multidrug resistance P-glycoprotein localized in the blood-brain barrier. When pure glucocorticoids became available, we managed to identify distinct populations of MR and GR in vitro. GR was found widely distributed in the brain and highly expressed in the typical stress centers. MR and GR are abundant and co-localized in limbic neurons [9, 10].

The MRs actually occur as glucocorticoid-preferring and aldosterone-selective variations in receptor function. Aldosterone-selectivity occurs solely in epithelial cells engaged in Na homeostasis. In a collaborative study with Edwards et al., we discovered in 1988 that aldosterone selectivity hinges on co-expression with the enzyme 11β-hydroxysteroid-dehydrogenase type 2 (HSD-2), which breaks down the naturally occurring glucocorticoids, cortisol and corticosterone, into their inactive 11-dehydro congeners [11]. The Australian group led by John Funder reached the same conclusion [12]. In the brain, the aldosterone-selective MRs involved in salt homeostasis are mostly restricted to neurons of the nucleus tractus solitarii (NTS) and the circumventricular organs. The MR-NTS neurons project to limbic forebrain regions, notably the locus coeruleus area involved in arousal and the bed nucleus of the stria terminalis (BNST). Via the BNST hub, the NTS neurons can affect emotions, memory performance, and reward processing [13, 14, 15].

A pharmacological amount of aldosterone, administered to rats, is anxiogenic and causes changes in coping with stress [16]. Such an effect can be explained by overstimulation of the aldosterone-responsive brain network. In fact, patients suffering from essential hypertension have an enhanced aldosterone secretion following stress exposure [17]. It would be of interest, therefore, to further explore this line of research, particularly in light of the persistent evidence of excess mineralocorticoids and aberrant MRs as risk factors for mood disorders [18, 19], also in patients with Conn’s syndrome [20]. In addition, the brain aldosterone MRs were found to be causal in hypertension in case a high-salt diet was offered [21], see overview on aldosterone and mineralocorticoid receptors [22].

The majority of MRs that are abundantly expressed in limbic-frontocortical neurons were identified as glucocorticoid-preferring. This is because cortisol and corticosterone are present in a 100–1000-fold excess over aldosterone, thus competing out aldosterone binding, even though part of the circulating glucocorticoid is bound to corticosteroid-binding globulin (CBG). Accordingly, these glucocorticoid-preferring MRs predominantly “see” the naturally occurring glucocorticoids, cortisol and corticosterone. Moreover, glucocorticoid preference is further enhanced by co-expression with HSD-1, which regenerates locally bioactive glucocorticoids from the inactive 11-dehydro congener [23]. Finally, MRs are promiscuous in that they bind in addition to glucocorticoids and aldosterone also progesterone and deoxycorticosterone. This promiscuity may be related to the fact that evolutionary the MRs preceded the GRs, progesterone receptors and androgen receptors [24].

Thus, some 30 years ago, we felt as if we were “digging gold.” We knew the precise localization of MR and GR in the brain and that these receptors did bind the same hormones—cortisol and corticosterone—but with an order of a magnitude difference in affinity. This was the start of a systematic search for their molecular, cellular, neuroendocrine, and behavioral function, together with the group of Marian Joëls in Amsterdam. This helped to define better the temporal, spatial, and contextual domains of the stress response that are so extremely important for understanding stress coping and adaptation [25, 26, 27, 28]. Before discussing MR/GR function, we will first briefly summarize the main aspects of their role in the molecular and cellular mechanisms of glucocorticoids.

Advertisement

3. Molecular mechanisms of MR-/GR-mediated actions

The non-genomic effects notwithstanding (see Section 4) MR and GR are best understood as transcription factors involved in the regulation of gene expression. Classically, their differential effects have been related to (besides cell-specific expression) transcriptional effects that are independent of the highly homologous DNA-binding domain. For example, an important part of the anti-inflammatory actions of GR activation depends on interactions of GR monomers with pro-inflammatory transcription factors such as the “nuclear factor kappa-light-chain-enhancer of activated B cells” (NF-κB), a process called transrepression, and these interactions are much weaker for MR [29]. Recently, the interaction of the GR monomer with NF-κB was challenged with the discovery of GR binding to “cryptic” DNA sequences within the genomic NF-κB response elements (κBREs) that mediate GR-driven repression of inflammatory gene expression [30].

Recent studies that evaluated MR and GR binding to the DNA in the hippocampus indicate that the receptors interact with the DNA via their—homologous—DNA-binding domains [31, 32, 33]. MR and GR share 96% homology in their DNA-binding domain, and both recognize the same “GRE” sequence in the DNA to which they bind as homo- or heterodimers. Yet, they differ in other parts of the protein, in particular in their large N-terminal domain. The best known target genes that are shared between MR and GR are FKBP5, Sgk1, GILZ, and PER1. For these genes, GR activation seems to extend the MR-mediated action by an order of magnitude, as shown in dose-response studies.

Based on genome-wide profiling, many corticosterone-responsive hippocampal mRNAs—also in laser-dissected subregions—are known, allowing the identification of specific signaling pathways [34, 35, 36, 37]. In other brain areas, information is more sparse, but likely will differ substantially, as patterns of MR and/or GR-responsive target genes overlap only partially between different cell types [38]. This cell specificity seems to be the consequence of a different chromatin organization and of cell-specific expression of coregulatory proteins that modulate the effects of MR and GR, once these are bound to the DNA [39, 40].

In view of their very different effects in the hippocampus, MR and GR should have unique target genes, and this assumption indeed recently has been materialized in three independent studies [31, 32, 41]. A unique signature of MR binding to DNA loci was discovered and found associated with the NeuroD transcription factor [33]. Also GR binding appeared associated to some extent with NeuroD, possibly as a result of heterodimer formation with MR [42]. Furthermore, current data suggest that NeuroD can interact with other unidentified proteins in the transcriptional complex that is formed upon MR binding to DNA. Such a MR-Neuro-D complex seems to confine specificity to cortisol action.

In spite of this progress in understanding receptor-specific cortisol actions, there is no single GR or MR target gene known to be responsible solely for circuit activation underlying a particular behavioral response during stress adaptation. Rather, MR and GR seem to be master regulators that mediate in complementary manner downstream regulatory networks in a cell- and context-specific fashion [37, 43]. Moreover, the transcriptional response of the hippocampal genome to corticosterone depends strongly on the recent past of the individual. About half of the significantly regulated mRNA’s were found to be different between animals with a recent history of stress, as compared to control animals [37, 44].

Advertisement

4. Cellular mechanisms of MR-/GR-mediated action

In hippocampal CA1 neurons, in particular the membrane properties affected by norepinephrine (NE), serotonin (5HT), and glutamate are affected by corticosterone in a U-shaped dose-response curve [45, 46]. Thus, the activation of 5HT1A receptors produced during absence of corticosterone a large increase in conductance of an inwardly rectifying K-channel, causing the membrane to hyperpolarize. MR activation with a low concentration of corticosterone minimized the 5HT1A hyperpolarization response [47]. When corticosterone levels increased and gradually occupied GR, the hyperpolarization response returned, but not in GRdim/dim mutants [48], in which cannot dimerize because of point mutation in their DNA domain [49]. A similar U-shaped dose response was found for the accommodation of firing frequency upon steady depolarization of cells by NE and for the Ca influx via L-type voltage-dependent channels [46, 50, 51, 52].

The U-shaped dose-response curve is not a common phenomenon in the brain, since it is dependent on the presence of both receptor types. Even if both receptors are present, such as in the dentate gyrus, other membrane properties are affected than in the CA1 neurons. In the dentate gyrus MR activation increased the field potential, and the single cell response showed activation of glutamatergic receptors, and both responses were not further affected by additional GR activation [46]. These cellular effects in CA1 and dentate gyrus have not been explained by transcriptional regulation. For instance, 5HT1A mRNA expression in CA1 cells was not affected by adrenalectomy, while it was in an MR-dependent fashion in dentate gyrus neurons [53].

The dentate gyrus is one of the two brain regions where neurogenesis occurs throughout life. In the absence of steroids, the turnover of these neurons increases, showing increased neurogenesis and apoptotic cell death. Both processes are normalized if the animals are replaced with low doses of corticosterone, just sufficient to occupy MR. Glucocorticoids suppress proliferation and migration of the newborn neurons via GRs. Lentiviral GR knockdown in the dentate progenitor cells accelerates neuronal differentiation and migration. The newborn neurons showed increased synaptic contacts and increased excitability and migrated further in establishing functional integration in the hippocampal circuitry. Accordingly, contextual fear-motivated behavior was impaired [54].

Regarding the non-genomic actions, MR mediates the rapid and transient increase of miniature excitatory postsynaptic currents (mEPSC) after treatment with corticosterone. The putative membrane MR is localized presynaptically and activates the release probability of glutamate. The rapid effects were eliminated after genetic deletion of the MR gene or with MR antagonists [55]. These effects are exerted by both aldosterone and corticosterone, and the dose-response curve suggests a lower affinity of steroid binding to the membrane than to nuclear MR. The membrane MR—in spite of much effort—has not been physically demonstrated yet [56, 57, 58] and likely is similar to the nuclear variant. The MR-enhanced increase of glutamate release downregulates the presynaptic metabotropic glutamate receptors (mGluR2) [59].

The nature of the membrane-mediated MR effects shows, however, large regional differences in the brain. For instance, in contrast to the rapid transient rise in excitability, the excitation is long-lasting in basolateral amygdala (BLA) neurons due to cooperation with genomic GR-mediated actions. Moreover, the duration of BLA excitation is further prolonged if—as is the case during stress—these cells are also exposed to NE, which can be mimicked by the β-adrenergic agonist isoproterenol. Interestingly, such a prolonged increased excitability of the BLA protects against the effect of a second MR-mediated corticosterone pulse, probably via rapid endocannabinoid action linked to the membrane GR [60]. These composite cellular responses were defined as a manifestation of “corticosterone metaplasticity” and may explain why emotions are so strongly remembered [61, 62].

Thus, the data demonstrate that glucocorticoid actions may vary between cell groups. This variety in responses also has consequences for the influence of stress exposure and stress hormones on long-term potentiation (LTP), a cellular model of memory performance. It demonstrates that stress does not a priori disturb LTP, since the outcome depends on the context, the previous experiences, the phase of the stress response, and the analyzed brain regions [63]. In the hippocampus, MR is essential for neuronal viability and maintenance of excitatory transmission. If, with increasing corticosterone concentrations, GR becomes occupied, this receptor restores transiently raised excitability.

Advertisement

5. Functional cooperation of MR and GR

MRs and GRs cooperate in glucocorticoid regulation, and below we will distinguish four different phases of this cooperation in stress coping and adaptation (see Figure 1). This distinction is based on temporal and contextual features of membrane and genomic glucocorticoid actions. The conditional nature is an important criterion, since it assigns a specificity to glucocorticoid action. The temporal action is also critical. The rapid non-genomic actions wax and wane in correspondence with glucocorticoid concentrations. The genomic actions develop minutes to hours after glucocorticoid exposure and may last for days or even a lifetime. The latter concerns aspects of programming of brain circuitry for later life by epigenetic processes at glucocorticoid targets or even the receptors themselves [66]. The following phases in glucocorticoid action can be distinguished:

Figure 1.

Four phases of MR/GR signaling in the brain during the stress response. Phase 1: “Basal” MR/GR signaling during ultradian/circadian activity is a determinant of the sensitivity of the stress response. Phase 2: “Onset” of the stress reaction non-genomic MR-mediated actions promotes appraisal processes, retrieval of previously stored information, selection of coping style, and encoding of the experience for learning, all directed to defend the “self.” Phase 3: “Termination” is the negative feedback action of GR-mediated glucocorticoid action aimed to prevent defense reactions from overshooting. Via GR, the experience is contextualized in the hippocampus and rationalized in the prefrontal cortex, with more “altruistic” solutions that increase motivation to assign a valence to social solutions and rewards. Phase 4: “Priming” refers to memory storage of the experience for future use (adapted from [27, 28, 64, 65]).

Phase 1—basal is the basal state in which during the circadian/ultradian cycle, mostly genomic MRs are occupied during the trough, and, subsequently, when glucocorticoid levels show their hourly increases, the hormone progressively activates additional GRs. The continuous MR activation is a determinant of the threshold or sensitivity of the stress response system. The transient GR activation by the hourly pulses maintains responsivity to sudden changes in glucocorticoid secretion as they occur in response to stress [3, 9, 67].

Phase 2—onset is the onset of the stress reaction when a novel experience is anticipated or actually happens and triggers sympathetic activation and CRH release. Non-genomic MRs that are rapidly activated by a stress-induced increase in circulating glucocorticoids enhance attention and vigilance to optimize sensory processing in support of perception and appraisal of novel information [68]. MR activation promotes memory retrieval in the hippocampus to deploy the previously used strategy in stress coping and enhances in amygdala emotional expressions of fear and aggression [69, 70]. MR activation also facilitates the choice of coping style. For instance, under mild stress conditions, most individuals will opt for a coping strategy involving the hippocampus (thinking). However, when stressors become more severe and less controllable, increasingly an emotion-driven habitual amygdala-striatal stimulus-response coping strategy is preferred (doing). The switch from “thinking to doing” depends on limbic MR. Corticosterone administration promotes habit formation, while MR antagonists prevent the switch and the slower, costlier hippocampal cognitive strategy is maintained. Finally, via MRs the context of the experience and the selected coping style are encoded for learning [71, 72, 73].

Phase 3—termination marks a further increase of glucocorticoid secretion and progressive activation of the lower-affinity membrane and genomic GRs, which are in limbic-frontocortical structures co-localized with MRs [25, 28]. The MRs are continuously involved in appraisal processes to monitor the outcome of the stress-coping strategy. GR function limits defense reactions to prevent these from overshoot that may cause damage, if not dampened [74]. These defense mechanisms are now abolished, and it is time for rationalization and contextualization of the experience and for assessment of valence as occurs in social interactions [27, 75]. At the same time, GR activation drives via a mitochondrial mechanism energy allocation to cells and circuits in need to facilitate recovery from the stressor [76]. This is a life-sustaining action since complete GR knockouts do not survive, while GRdim/dim do. After all, lack of glucocorticoids is not compatible with life as is illustrated by adrenalectomy and in the case of Addison’s disease. Phase 3 is also characterized by increased motivational arousal, emotional expressions, and reinforcement learning, accompanied by increased gene expression of key components in the amygdala (re: enhanced CRH expression) and ventral striatum—frontocortical circuitry (re: increased dopaminergic function) [77, 78, 79, 80, 81].

Phase 4—priming GR activation in the limbic-frontocortical circuits promotes storage of contextual and emotional-loaded information in the memory. This consolidation process takes a couple of hours after the stressful experience [82]. Synaptic adaptations occur which can be measured with fMRI and are characterized by genome-wide transcriptional signatures [83, 84, 85]. Growth factors such as BDNF participate by acting in the dentate neurogenic niche; also growth factor actions in e.g. mPFC and mesolimbic dopaminergic systems [86, 87] are all involved. Hence, GR-activated memory storage prepares for the future, so that stored information can be retrieved again in the proper context. During phases 3 and 4, the individual’s homeostasis is restored and behavioral adaptation is promoted [4].

Using optogenetics combined with neuroanatomical tracing, the top-down organization of the brain’s coping circuitry is rapidly unraveled today. Accordingly, the prelimbic mPFC sends excitatory projections to the lateroventral (av)-BNST, which operates as an inhibitory GABAergic hub over downstream neuroendocrine, autonomic, and behavioral responses [88]. Stressors activate the excitatory output of the mPFC, which translates into BNST-dependent inhibition of CRH neurons in the PVN and results in suppression of the HPA axis response. In another group of CRH neurons, the BNST input attenuates the sympathetic output. A separate pathway of the BNST projects to the ventrolateral periaqueductal (vl-PAG) where passive coping is promoted at the expense of the initial active coping strategy [89, 90]. Active coping refers to fight or flight, which, when the situation is appraised as inescapable, causes a reorganization of prelimbic to infralimbic mPFC circuitry that is aimed to restrain the emotional and autonomic responses [91, 92, 93, 94]. Passive conservation withdrawal behavior is promoted allowing recuperation and storage of energy resources [95, 96].

This coping circuit is modulated in function by contextual information from the hippocampus, by emotional- and fear-input from the amygdala, visceral and autonomous inputs from the brain stem, and motivational arousal associated with valence assessment from the ventral striatum. The coping circuit and its modulating inputs are all targets of the glucocorticoids that convey environmental and physiological information. This bottom-up control exerted by the glucocorticoids is mediated by the MR and GR in a complementary manner along the four different phases of stress coping and adaptation [64] (see Figure 1). The action of the glucocorticoid during stress coping and adaptation has led to the formulation of the MR/GR balance hypothesis, which states that “upon imbalance of the MR- and GR-mediated actions, the initiation and/or management of the stress response becomes compromised. At a certain threshold this may lead to a condition of neuroendocrine dysregulation and impaired behavioral adaptation, which potentially can aggravate stress-related deterioration and promote vulnerability” [9, 25, 28, 97, 98, 99].

Advertisement

6. Implications for pathogenesis and treatment of stress-related diseases

Physical or psychogenic stressors promote activation of circuits that underlie appraisal and decision-making processes, which are important for selection of an appropriate coping style to support physiological and behavioral adaptations. The most severe psychogenic stressor is lack of control and inability to predict, with an uncertain fearful feeling [96, 100]. The brain can adapt to this situation by proliferation of the emotional amygdala and atrophy of the hippocampus, ventral striatum, and prefrontal cortex [101, 102, 103, 104]. Glucocorticoid secretion remains elevated and energy resources are drained. Essential defense mechanisms become compromised, and when then confronted with a novel stressor, coping fails, breakdown of adaptation is facilitated, and vulnerability to mood and anxiety disorders increases [105, 106].

Adverse (early) life experience and unfavorable socioeconomic conditions are important predisposing factors for such stress-related disorders [107]. Also genetic variants and epigenetic modifications are increasingly recognized as biomarkers of susceptibility and vulnerability. For instance, for MR, two functional SNPs (rs2070951 and rs5522) constitute a block of four haplotypes. Haplotype 2 generates in vitro the highest MR-binding capacity and transactivation. Carriers of haplotype 2 display a preferential habit rather than cognitive strategy in coping with stress. Haplotype 2 (C/A frequency 35%) is associated with optimism and protection to depression and predicts a higher efficacy of antidepressants [73, 108, 109, 110]. Actually, the MR is a promising target to facilitate the action of antidepressants [111].

Progress is made in exploiting the relevance of the MR/GR balance for devising preventive or curative strategies in the treatment of mental health. For instance, it is recognized that patients under dexamethasone therapy have very low levels of endogenous circulating glucocorticoids. While dexamethasone is a potent GR ligand, the MR becomes depleted of endogenous hormone, because of suppression of the HPA axis. Refill of the MR with cortisol add-on largely eliminates the psychologic/psychiatric side effects of dexamethasone therapy [112, 113, 114, 115]. Alternatively, the glucocorticoid/progesterone antagonist mifepristone is applied for treatment of hyperglycemia in patients suffering from Cushing’s syndrome [116]. Recently, selective GR modulators (SGRMs) became available that can target metabolism but do not show side effects on pituitary ACTH release [117, 118, 119].

Advertisement

7. Concluding remarks

Glucocorticoids, acting via brain MRs and GRs, coordinate multiple functions over time with one single goal: to promote stress coping and adaptation. Imbalance in the MR-/GR-mediated signaling pathways increases susceptibility to stress-related mental and neurodegenerative disorders. These imbalances develop under conditions of chronic stress when top-down control exerted by the mPFC over the stress-coping circuitry is compromised and the cost of bottom-up glucocorticoid action exceeds its benefit. New SGRMs are being developed that target the tissue- and context-specific action of glucocorticoids in specific domains of cognition, emotion, and motivation and which may assist in targeted therapies of stress-related mental disorders.

Advertisement

Acknowledgments

This publication is based upon the work from the EU COST Action ADMIRE BM1301 in Aldosterone and Mineralocorticoid Receptor (MR) Physiology and Pathophysiology (www.admirecosteu.com). The Royal Netherlands Academy of Arts and Sciences (ERdK), NWO, and ZONMW (OCM) are gratefully acknowledged.

Advertisement

Conflict of interest

ERdK is on the Scientific Advisory Board of the DynaCorts Group and owns stock of Corcept Therapeutics. OCM receives funding from Corcept Therapeutics.

References

  1. 1. Sarabdjitsingh RA, Isenia S, Polman A, Mijalkovic J, Lachize S, Datson N, et al. Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain. Endocrinology. 2010;151:1177-1186. DOI: 10.1210/en.2009-1119
  2. 2. Lightman SL, Conway-Campbell BL. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nature Reviews. Neuroscience. 2010;11:710-718. DOI: 10.1038/nrn2914
  3. 3. Sarabdjitsingh RA, Jezequel J, Pasricha N, Mikasova L, Kerkhofs A, Karst H, et al. Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity. Proceedings of the National Academy of Sciences. 2014;111:14265-14270. DOI: 10.1073/pnas.1411216111
  4. 4. de Kloet ER, Joëls M, Holsboer F. Stress and the brain: From adaptation to disease. Nature Reviews. Neuroscience. 2005;6:463-475. DOI: 10.1038/nrn1683
  5. 5. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nature Reviews. Neuroscience. 2009;10:397-409. DOI: 10.1038/nrn2647
  6. 6. McEwen BS, Weiss JM, Schwartz LS. Selective retention of corticosterone by limbic structures in rat brain. Nature. 1968;220:911-912. DOI: 10.1038/220911a0
  7. 7. Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation. Endocrinology. 1985;117:2505-2511. DOI: 10.1210/endo-117-6-2505
  8. 8. Arriza JL, Weinberger C, Cerelli G, Glaser TM, Handelin BL, Housman DE, et al. Cloning of human mineralocorticoid receptor complementary DNA: Structural and functional kinship with the glucocorticoid receptor. Science. 1987;237:268-275. DOI: 10.1126/science.3037703
  9. 9. De Kloet ER, Reul JMHM. Feedback action and tonic influence of corticosteroids on brain function: A concept arising from the heterogeneity of brain receptor systems. Psychoneuroendocrinology. 1987;12:83-105. DOI: 10.1016/0306-4530(87)90040-0
  10. 10. Meijer OC, De Lange ECM, Breimer DD, De Boer AG, Workel JO, De Kloet ER. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology. 1998;139:1789-1793. DOI:10.1210/endo.139.4.5917
  11. 11. Edwards CR, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, et al. Localisation of 11 beta-hydroxysteroid dehydrogenase—Tissue specific protector of the mineralocorticoid receptor. Lancet (London, England). 1988;2:986-989. DOI: 10.1016/S0140-6736(88)90742-8
  12. 12. Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: Target tissue specificity is enzyme, not receptor, mediated. Science. 1988;242:583-585. DOI: 10.1126/science.2845584
  13. 13. Krause EG, Sakai RR. Richter and sodium appetite: From adrenalectomy to molecular biology. Appetite. 2007;49:353-367. DOI: 10.1016/j.appet.2007.01.015
  14. 14. Geerling JC, Loewy AD. Aldosterone in the brain. AJP Renal Physiology. 2009;297:F559-F576. DOI: 10.1152/ajprenal.90399.2008
  15. 15. Gasparini S, Resch JM, Narayan SV, Peltekian L, Iverson GN, Karthik S, et al. Aldosterone-sensitive HSD2 neurons in mice. Brain Structure & Function. 2019;224:387-417. DOI: 10.1007/s00429-018-1778-y
  16. 16. Hlavacova N, Jezova D. Chronic treatment with the mineralocorticoid hormone aldosterone results in increased anxiety-like behavior. Hormones and Behavior. 2008;54:90-97. DOI: 10.1016/j.yhbeh.2008.02.004
  17. 17. Markou A, Sertedaki A, Kaltsas G, Androulakis II, Marakaki C, Pappa T, et al. Stress-induced aldosterone hyper-secretion in a substantial subset of patients with essential hypertension. The Journal of Clinical Endocrinology and Metabolism. 2015;100:2857-2864. DOI: 10.1210/jc.2015-1268
  18. 18. de Kloet ER, Joëls M. Brain mineralocorticoid receptor function in control of salt balance and stress-adaptation. Physiology & Behavior. 2017;178:13-20. DOI: 10.1016/j.physbeh.2016.12.045
  19. 19. Murck H, Schüssler P, Steiger A. Renin-angiotensin-aldosterone system: The forgotten stress hormone system: Relationship to depression and sleep. Pharmacopsychiatry. 2012;45:83-95. DOI: 10.1055/s-0031-1291346
  20. 20. Künzel HE, Apostolopoulou K, Pallauf A, Gerum S, Merkle K, Schulz S, et al. Quality of life in patients with primary aldosteronism: Gender differences in untreated and long-term treated patients and associations with treatment and aldosterone. Journal of Psychiatric Research. 2012;46:1650-1654. DOI: 10.1016/j.jpsychires.2012.08.025
  21. 21. Evans LC, Ivy JR, Wyrwoll C, McNairn JA, Menzies RI, Christensen TH, et al. Conditional deletion of Hsd11b2 in the brain causes salt appetite and hypertension. Circulation. 2016;133:1360-1370. DOI: 10.1161/CIRCULATIONAHA.115.019341
  22. 22. Jaisser F, Farman N. Emerging roles of the mineralocorticoid receptor in pathology: Toward new paradigms in clinical pharmacology. Pharmacological Reviews. 2016;68:49-75. DOI: 10.1124/pr.115.011106
  23. 23. Chapman K, Holmes M, Seckl J. 11-Hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action. Physiological Reviews. 2013;93:1139-1206. DOI: 10.1152/physrev.00020.2012
  24. 24. Baker ME, Funder JW, Kattoula SR. Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors. The Journal of Steroid Biochemistry and Molecular Biology. 2013;137:57-70. DOI: 10.1016/j.jsbmb.2013.07.009
  25. 25. de Kloet ER. Brain corticosteroid receptor balance and homeostatic control. Frontiers in Neuroendocrinology. 1991;12:95-164. DOI: 10.1080/09614520701469617
  26. 26. Joëls M, de Kloet ER. 30 years of the mineralocorticoid receptor: The brain mineralocorticoid receptor: A saga in three episodes. The Journal of Endocrinology. 2017;234:T49-T66. DOI: 10.1530/JOE-16-0660
  27. 27. Joëls M, Karst H, Sarabdjitsingh RA. The stressed brain of humans and rodents. Acta Physiologica (Oxford, England). 2018;223:e13066. DOI: 10.1111/apha.13066
  28. 28. de Kloet ER, Meijer OC, de Nicola AF, de Rijk RH, Joëls M. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Frontiers in Neuroendocrinology. 2018;49:124-145. DOI: 10.1016/j.yfrne.2018.02.003
  29. 29. D. Pearce, K.R. Yamamoto, Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response element, Science (New York, N.Y.). 259 (1993) 1161-1165. DOI: 10.1126/science.8382376
  30. 30. Hudson WH, de Vera IMS, Nwachukwu JC, Weikum ER, Herbst AG, Yang Q , et al. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. Nature Communications. 2018;9:1337. DOI: 10.1038/s41467-018-03780-1
  31. 31. Polman JAE, de Kloet ER, Datson NA. Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome. Endocrinology. 2013;154:1832-1844. DOI: 10.1210/en.2012-2187
  32. 32. Pooley JR, Flynn BP, Grøntved L, Baek S, Guertin MJ, Kershaw YM, et al. Genome-wide identification of basic helix-loop helix and NF-1 motifs underlying GR binding sites in male rat hippocampus. Endocrinology. 2017;158:1486-1501. DOI: 10.1210/en.2016-1929
  33. 33. van Weert LTCM, Buurstede JC, Mahfouz A, Braakhuis PSM, Polman JAE, Sips HCM, et al. NeuroD factors discriminate mineralocorticoid from glucocorticoid receptor DNA binding in the male rat brain. Endocrinology. 2017;158:1511-1522. DOI: 10.1210/en.2016-1422
  34. 34. Datson NA, Van Der Perk J, De Kloet ER, Vreugdenhil E. Identification of corticosteroid-responsive genes in rat hippocampus using serial analysis of gene expression. The European Journal of Neuroscience. 2001;14:675-689. DOI: 10.1046/j.0953-816x.2001.01685.x
  35. 35. Datson NA, Morsink MC, Meijer OC, de Kloet ER. Central corticosteroid actions: Search for gene targets. European Journal of Pharmacology. 2008;583:272-289. DOI: 10.1016/j.ejphar.2007.11.070
  36. 36. Datson NA, Speksnijder N, Mayer JL, Steenbergen PJ, Korobko O, Goeman J, et al. The transcriptional response to chronic stress and glucocorticoid receptor blockade in the hippocampal dentate gyrus. Hippocampus. 2012;22:359-371. DOI: 10.1002/hipo.20905
  37. 37. Datson NA, van den Oever JME, Korobko OB, Magarinos AM, De Kloet ER, Mcewen B. Prior history of chronic stress changes the transcriptional response to glucocorticoid challenge in the dentate gyrus region of the male rat hippocampus. Endocrinology. 2013;154:3261-3272. DOI: 10.1210/en.2012-2233
  38. 38. S. John, P.J. Sabo, R.E. Thurman, M.-H. Sung, S.C. Biddie, T.A. Johnson, G.L. Hager, J.A. Stamatoyannopoulos, Chromatin accessibility pre-determines glucocorticoid receptor binding patterns TL-43, Nature Genetics. 2011;43:264-268. DOI: 10.1038/ng.759
  39. 39. Mahfouz A, Lelieveldt BPF, Grefhorst A, van Weert LTCM, Mol IM, Sips HCM, et al. Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions. Proceedings of the National Academy of Sciences of the United States of America. 2016;113:2738-2743. DOI: 10.1073/pnas.1520376113
  40. 40. Zalachoras I, Verhoeve SL, Toonen LJ, van Weert LTCM, van Vlodrop AM, Mol IM, et al. Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH expression. Molecular Psychiatry. 2016;21:1733-1739. DOI: 10.1038/mp.2016.16
  41. 41. Polman JAE, Hunter RG, Speksnijder N, van den Oever JME, Korobko OB, McEwen BS, et al. Glucocorticoids modulate the mTOR pathway in the hippocampus: Differential effects depending on stress history. Endocrinology. 2012;153:4317-4327. DOI: 10.1210/en.2012-1255
  42. 42. Mifsud KR, Reul JMHM. Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus. Proceedings of the National Academy of Sciences of the United States of America. 2016;113:11336-11341. DOI: 10.1073/pnas.1605246113
  43. 43. Repunte-Canonigo V, Shin W, Vendruscolo LF, Lefebvre C, van der Stap L, Kawamura T, et al. Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks. Genome Biology. 2015;16:68. DOI: 10.1186/s13059-015-0593-5
  44. 44. Gray JD, Kogan JF, Marrocco J, McEwen BS. Genomic and epigenomic mechanisms of glucocorticoids in the brain. Nature Reviews. Endocrinology. 2017;13:661-673. DOI: 10.1038/nrendo.2017.97
  45. 45. Joëls M, de Kloet ER. Control of neuronal excitability by corticosteroid hormones. Trends in Neurosciences. 1992;15:25-30. DOI: 10.1016/0166-2236(92)90345-9
  46. 46. Joëls M. Corticosteroid effects in the brain: U-shape it. Trends in Pharmacological Sciences. 2006;27:244-250. DOI: 10.1016/j.tips.2006.03.007
  47. 47. Joels M, Hesen W, De Kloet ER. Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA 1 neurons. The Journal of Neuroscience. 1991;11:2288-2294. doi.org/10.1523/JNEUROSCI.11-08-02288
  48. 48. Karst H, Karten YJ, Reichardt HM, de Kloet ER, Schutz G, Joels M. Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers. Nature Neuroscience. 2000;3:977-978. DOI: 10.1038/79910
  49. 49. Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, et al. DNA binding of the glucocorticoid receptor is not essential for survival. Cell. 1998;93:531-541. DOI: 10.1016/S0092-8674(00)81183-6
  50. 50. Joëls M, de Kloet ER. Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science. 1989;245:1502-1505. DOI: 10.1126/science.2781292
  51. 51. Joëls M, de Kloet ER. Mineralocorticoid receptor-mediated changes in membrane properties of rat CA1 pyramidal neurons in vitro. Proceedings of the National Academy of Sciences of the United States of America. 1990;87:4495-4498. DOI: 10.1073/pnas.87.12.4495
  52. 52. Joëls M, Sarabdjitsingh RA, Karst H.Unraveling the time domains of corticosteroid hormone influences on brain activity: Rapid, slow, and chronic modes. Pharmacological Reviews. 2012;64:901-938. DOI: 10.1124/pr.112.005892
  53. 53. Meijer OC, de Kloet ER. A role for the mineralocorticoid receptor in a rapid and transient suppression of hippocampal 5-HT1A receptor mRNA by corticosterone. Journal of Neuroendocrinology. 1995;7:653-657. DOI: 10.1111/j.1365-2826.1995.tb00804.x
  54. 54. Fitzsimons CP, Van Hooijdonk LWA, Schouten M, Zalachoras I, Brinks V, Zheng T, et al. Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior. Molecular Psychiatry. 2013;18:993-1005. DOI: 10.1038/mp.2012.123
  55. 55. Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proceedings of the National Academy of Sciences. 2005;102:19204-19207. DOI: 10.1073/pnas.0507572102
  56. 56. Groeneweg FL, Karst H, de Kloet ER, Joëls M. Rapid non-genomic effects of corticosteroids and their role in the central stress response. The Journal of Endocrinology. 2011;209:153-167. DOI: 10.1530/JOE-10-0472
  57. 57. Groeneweg FL, Karst H, de Kloet ER, Joëls M. Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Molecular and Cellular Endocrinology. 2012;350:299-309. DOI: 10.1016/j.mce.2011.06.020
  58. 58. Groeneweg FL, van Royen ME, Fenz S, Keizer VIP, Geverts B, Prins J, et al. Quantitation of glucocorticoid receptor DNA-binding dynamics by single-molecule microscopy and FRAP. PLoS ONE. 2014;9:e90532. DOI: 10.1371/journal.pone.0090532
  59. 59. Nasca C, Zelli D, Bigio B, Piccinin S, Scaccianoce S, Nisticò R, et al. Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proceedings of the National Academy of Sciences. 2015;112:14960-14965. DOI: 10.1073/pnas.1516016112
  60. 60. Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012;204:5-16. DOI: 10.1016/j.neuroscience.2011.12.030
  61. 61. Karst H, Berger S, Erdmann G, Schütz G, Joëls M. Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:14449-14454. DOI: 10.1073/pnas.0914381107
  62. 62. Karst H, Joëls M. Severe stress hormone conditions cause an extended window of excitability in the mouse basolateral amygdala. Neuropharmacology. 2016;110:175-180. DOI: 10.1016/j.neuropharm.2016.07.027
  63. 63. Joëls M, Krugers HJ. LTP after stress: Up or down? Neural Plasticity. 2007;2007:93202. DOI: 10.1155/2007/93202
  64. 64. de Kloet ER, de Kloet SF, de Kloet CS, de Kloet AD. Top-down and bottom-up control of stress-coping. Journal of Neuroendocrinology. 2019;31:e12675. DOI: 10.1111/jne.12675
  65. 65. Molendijk ML, de Kloet ER. Coping with the forced swim stressor: Current state-of-the-art. Behavioural Brain Research. 2019;364:1-10. DOI: 10.1016/j.bbr.2019.02.005
  66. 66. Turecki G, Meaney MJ. Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry. 2016;79:87-96. DOI: 10.1016/j.biopsych.2014.11.022
  67. 67. Sarabdjitsingh RA, Conway-Campbell BL, Leggett JD, Waite EJ, Meijer OC, De Kloet ER, et al. Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Endocrinology. 2010. DOI: 10.1210/en.2010-0832
  68. 68. Cornelisse S, Joëls M, Smeets T. A randomized trial on mineralocorticoid receptor blockade in men: Effects on stress responses, selective attention, and memory. Neuropsychopharmacology. 2011;36:2720-2728. DOI: 10.1038/npp.2011.162
  69. 69. Korte SM, De Boer SF, De Kloet ER, Bohus B. Anxiolytic-like effects of selective mineralocorticoid and glucocorticoid antagonists on fear-enhanced behavior in the elevated plus-maze. Psychoneuroendocrinology. 1995;20:385-394. DOI: 10.1016/0306-4530(94)00069-7
  70. 70. Kruk MR, Haller J, Meelis W, de Kloet ER. Mineralocorticoid receptor blockade during a rat’s first violent encounter inhibits its subsequent propensity for violence. Behavioral Neuroscience. 2013;127:505-514. DOI: 10.1037/a0033553
  71. 71. Oitzl MS, de Kloet ER. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning. Behavioral Neuroscience. 1992;106:62-71. DOI: 10.1037/0735-7044.106.1.62
  72. 72. Schwabe L, Schächinger H, de Kloet ER, Oitzl MS. Corticosteroids operate as a switch between memory systems. Journal of Cognitive Neuroscience. 2010;22:1362-1372. DOI: 10.1162/jocn.2009.21278
  73. 73. Wirz L, Reuter M, Wacker J, Felten A, Schwabe L. A haplotype associated with enhanced mineralocorticoid receptor expression facilitates the stress-induced shift from “cognitive” to “habit” learning. eNeuro. 2017;4. DOI: 10.1523/ENEURO.0359-17.2017
  74. 74. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocrine Reviews. 2000;21:55-89. DOI: 10.1210/er.21.1.55
  75. 75. Weger M, Sandi C. High anxiety trait: A vulnerable phenotype for stress-induced depression. Neuroscience and Biobehavioral Reviews. 2018;87:27-37. DOI: 10.1016/j.neubiorev.2018.01.012
  76. 76. Hollis F, van der Kooij MA, Zanoletti O, Lozano L, Cantó C, Sandi C. Mitochondrial function in the brain links anxiety with social subordination. Proceedings of the National Academy of Sciences. 2015;112:15486-15491. DOI: 10.1073/pnas.1512653112
  77. 77. Makino S, Gold PW, Schulkin J. Effects of corticosterone on CRH mRNA and content in the bed nucleus of the stria terminalis; comparison with the effects in the central nucleus of the amygdala and the paraventricular nucleus of the hypothalamus. Brain Research. 1994;657:141-149. DOI: 10.1016/0006-8993(94)90961-x
  78. 78. Piazza PV, Le Moal ML. Pathophysiological basis of vulnerability to drug abuse: Role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annual Review of Pharmacology and Toxicology. 1996;36:359-378. DOI: 10.1146/annurev.pa.36.040196.002043
  79. 79. Lachize S, Apostolakis EM, van der Laan S, Tijssen AMI, Xu J, de Kloet ER, et al. Steroid receptor coactivator-1 is necessary for regulation of corticotropin-releasing hormone by chronic stress and glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:8038-8042. DOI: 10.1073/pnas.0812062106
  80. 80. Barik J, Marti F, Morel C, Fernandez SP, Lanteri C, Godeheu G, et al. Chronic stress triggers social aversion via glucococorticoid receptor in dopaminoceptive neurons. Science. 2013;(80).339:332-335. DOI: 10.1007/s13398-014-0173-7.2
  81. 81. Bagot RC, Parise EM, Peña CJ, Zhang H-X, Maze I, Chaudhury D, et al. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nature Communications. 2015;6:7062. DOI: 10.1038/ncomms8062
  82. 82. De Quervain D, Schwabe L, Roozendaal B. Stress, glucocorticoids and memory: Implications for treating fear-related disorders. Nature Reviews. Neuroscience. 2016;18:7-19. DOI: 10.1038/nrn.2016.155
  83. 83. Datson NA, Morsink MC, Steenbergen PJ, Aubert Y, Schlumbohm C, Fuchs E, et al. A molecular blueprint of gene expression in hippocampal subregions CA1, CA3, and DG is conserved in the brain of the common marmoset. Hippocampus. 2009;19:739-752. DOI: 10.1002/hipo.20555
  84. 84. Henckens MJAG, Pu Z, Hermans EJ, Van Wingen GA, Joëls M, Fernández G. Dynamically changing effects of corticosteroids on human hippocampal and prefrontal processing. Human Brain Mapping. 2012;33:2885-2897. DOI: 10.1002/hbm.21409
  85. 85. Hermans EJ, Henckens MJ, Joels M, Fernandez G. Dynamic adaptation of large-scale brain networks in response to acute stressors. Trends in Neurosciences. 2014;37:304-314. DOI: 10.1016/j.tins.2014.03.006
  86. 86. Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391-404. DOI: 10.1016/j.cell.2007.09.018
  87. 87. Lucassen PJ, Pruessner J, Sousa N, Almeida OFX, Van Dam AM, Rajkowska G, et al. Neuropathology of stress. Acta Neuropathologica. 2014;127:109-135. DOI: 10.1007/s00401-013-1223-5
  88. 88. Radley JJ, Johnson SB. Anteroventral bed nuclei of the stria terminalis neurocircuitry: Towards an integration of HPA axis modulation with coping behaviors—Curt Richter Award Paper 2017. Psychoneuroendocrinology. 2018;89:239-249. DOI: 10.1016/j.psyneuen.2017.12.005
  89. 89. Keay KA, Bandler R. Parallel circuits mediating distinct emotional coping reactions to different types of stress. Neuroscience and Biobehavioral Reviews. 2001;25:669-678. DOI: 10.1016/S0149-7634(01)00049-5
  90. 90. Johnson SB, Emmons EB, Lingg RT, Anderson RM, Romig-Martin SA, LaLumiere RT, et al. Prefrontal-bed nucleus circuit modulation of a passive coping response set. The Journal of Neuroscience. 2019;39:1405-1419. DOI: 10.1523/JNEUROSCI.1421-18.2018
  91. 91. Fiore VG, Mannella F, Mirolli M, Latagliata EC, Valzania A, Cabib S, et al. Corticolimbic catecholamines in stress: A computational model of the appraisal of controllability. Brain Structure & Function. 2015;220:1339-1353. DOI: 10.1007/s00429-014-0727-7
  92. 92. McKlveen JM, Morano RL, Fitzgerald M, Zoubovsky S, Cassella SN, Scheimann JR, et al. Chronic stress increases prefrontal inhibition: A mechanism for stress-induced prefrontal dysfunction. Biological Psychiatry. 2016;80:754-764. DOI: 10.1016/j.biopsych.2016.03.2101
  93. 93. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: Ten years of progress. Annual Review of Psychology. 2012;63:129-151. DOI: 10.1146/annurev.psych.121208.131631
  94. 94. Wood M, Adil O, Wallace T, Fourman S, Wilson SP, Herman JP, et al. Infralimbic prefrontal cortex structural and functional connectivity with the limbic forebrain: A combined viral genetic and optogenetic analysis. Brain Structure & Function. 2019;224:73-97. DOI: 10.1007/s00429-018-1762-6
  95. 95. Henry J, Stephens P. Stress, Health and the Social Environment: A Sociobiological Approach. New York: Springer; 1977. DOI: https://doi.org/10.1007/978-1-4612-6363-
  96. 96. de Boer SF, Buwalda B, Koolhaas JM. Untangling the neurobiology of coping styles in rodents: Towards neural mechanisms underlying individual differences in disease susceptibility. Neuroscience and Biobehavioral Reviews. 2017;74:401-422. DOI: 10.1016/j.neubiorev.2016.07.008
  97. 97. De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocrine Reviews. 1998;19:269-301. DOI: 10.1210/edrv.19.3.0331
  98. 98. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477-501. DOI: 10.1016/S0893-133X(00)00159-7
  99. 99. de Kloet ER. From receptor balance to rational glucocorticoid therapy. Endocrinology. 2014;155:2754-2769. DOI: 10.1210/en.2014-1048
  100. 100. Peters A, McEwen BS, Friston K. Uncertainty and stress: Why it causes diseases and how it is mastered by the brain. Progress in Neurobiology. 2017;156:164-188. DOI: 10.1016/j.pneurobio.2017.05.004
  101. 101. McEwen BS. Physiology and neurobiology of stress and adaptation: Central role of the brain. Physiological Reviews. 2007;87:873-904. DOI: 10.1152/physrev.00041.2006
  102. 102. McEwen BS. Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course. Frontiers in Neuroendocrinology. 2018;49:8-30. DOI: 10.1016/j.yfrne.2017.11.001
  103. 103. Sousa N. The dynamics of the stress neuromatrix. Molecular Psychiatry. 2016;21:302-312. DOI: 10.1038/mp.2015.196
  104. 104. Magalhães R, Barrière DA, Novais A, Marques F, Marques P, Cerqueira J, et al. The dynamics of stress: A longitudinal MRI study of rat brain structure and connectome. Molecular Psychiatry. 2018;23:1998-2006. DOI: 10.1038/mp.2017.244
  105. 105. Karatsoreos IN, McEwen BS. Psychobiological allostasis: Resistance, resilience and vulnerability. Trends in Cognitive Sciences. 2011;15:576-584. DOI: 10.1016/j.tics.2011.10.005
  106. 106. Picard M, McEwen BS, Epel ES, Sandi C. An energetic view of stress: Focus on mitochondria. Frontiers in Neuroendocrinology. 2018;49:72-85. DOI: 10.1016/j.yfrne.2018.01.001
  107. 107. McEwen BS, Gianaros PJ. Stress- and Allostasis-induced brain plasticity. Annual Review of Medicine. 2011;62:431-445. DOI: 10.1146/annurev-med-052209-100430
  108. 108. Klok MD, Giltay EJ, Van der Does AJW, Geleijnse JM, Antypa N, Penninx BWJH, et al. A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Translational Psychiatry. 2011;1:e62. DOI: 10.1038/tp.2011.59
  109. 109. de Kloet ER, Otte C, Kumsta R, Kok L, Hillegers MHJ, Hasselmann H, et al. Stress and depression: A crucial role of the mineralocorticoid receptor. Journal of Neuroendocrinology. 2016;28:8. DOI: 10.1111/jne.12379
  110. 110. Kumsta R, Kliegel D, Linden M, DeRijk R, de Kloet ER. Genetic variation of the mineralocorticoid receptor gene (MR, NR3C2) is associated with a conceptual endophenotype of “CRF-hypoactivity”. Psychoneuroendocrinology. 2018. DOI: 10.1016/j.psyneuen.2018.09.036
  111. 111. Otte C, Hinkelmann K, Moritz S, Yassouridis A, Jahn H, Wiedemann K, et al. Modulation of the mineralocorticoid receptor as add-on treatment in depression: A randomized, double-blind, placebo-controlled proof-of-concept study. Journal of Psychiatric Research. 2010;44:339-346. DOI: 10.1016/j.jpsychires.2009.10.006
  112. 112. Born J, DeKloet ER, Wenz H, Kern W, Fehm HL. Gluco- and antimineralocorticoid effects on human sleep: A role of central corticosteroid receptors. The American Journal of Physiology. 1991;260:E183-E188
  113. 113. Groch S, Wilhelm I, Lange T, Born J. Differential contribution of mineralocorticoid and glucocorticoid receptors to memory formation during sleep. Psychoneuroendocrinology. 2013;38:2962-2972. DOI: 10.1016/j.psyneuen.2013.08.006
  114. 114. Warris LT, Van Den Heuvel-Eibrink MM, Aarsen FK, Pluijm SMF, Bierings MB, Den Van Bos C, et al. Hydrocortisone as an intervention for dexamethasone-induced adverse effects in pediatric patients with acute lymphoblastic leukemia: Results of a double-blind, randomized controlled trial. Journal of Clinical Oncology. 2016;34:2287-2293. DOI: 10.1200/JCO.2015.66.0761
  115. 115. Meijer OC, de Kloet ER. A refill for the brain mineralocorticoid receptor: The benefit of cortisol add-on to dexamethasone therapy. Endocrinology. 2017;158:448-454. DOI: 10.1210/en.2016-1495
  116. 116. Moraitis AG, Block T, Nguyen D, Belanoff JK. The role of glucocorticoid receptors in metabolic syndrome and psychiatric illness. The Journal of Steroid Biochemistry and Molecular Biology. 2017;165:114-120. DOI: 10.1016/j.jsbmb.2016.03.023
  117. 117. Kroon J, Koorneef LL, van den Heuvel JK, Verzijl CRC, van de Velde NM, Mol IM, et al. Selective glucocorticoid receptor antagonist CORT125281 activates brown adipose tissue and alters lipid distribution in male mice. Endocrinology. 2018;159:535-546. DOI: 10.1210/en.2017-00512
  118. 118. Nguyen ET, Streicher J, Berman S, Caldwell JL, Ghisays V, Estrada CM, et al. A mixed glucocorticoid/mineralocorticoid receptor modulator dampens endocrine and hippocampal stress responsivity in male rats. Physiology & Behavior. 2017;178:82-92. DOI: 10.1016/j.physbeh.2017.01.020
  119. 119. Meijer OC, Koorneef LL, Kroon J. Glucocorticoid receptor modulators. Annales d'Endocrinologie. 2018;79:107-111. DOI: 10.1016/j.ando.2018.03.004

Written By

Edo R. de Kloet and Onno C. Meijer

Submitted: 22 May 2019 Reviewed: 04 June 2019 Published: 25 September 2019

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License, which permits use, distribution and reproduction for non-commercial purposes, provided the original is properly cited.

Continue reading from the same book

View All
Chapter 11 View on Aldosterone and the Brain Revisited

By Natasa Hlavacova and Damiela Jezova

868 downloads

Chapter 12 Transcriptional Regulation and Epigenetics in Card...

By Lisa Deng, Lutz Hein and Achim Lother

838 downloads

Chapter 13 MicroRNAs in Aldosterone Production and Action

By Scott M. MacKenzie, Josie van Kralingen, Hannah Ma...

786 downloads