Mineralocorticoid Receptors and Glucocorticoid Receptors in HPA Stress Responses During Coping and Adaptation
Summary and Keywords
The glucocorticoid hormones cortisol and corticosterone coordinate circadian events and are master regulators of the stress response. These actions of the glucocorticoids are mediated by mineralocorticoid receptors (NR3C2, or MRs) and glucocorticoid receptors (NR3C1, or GRs). MRs bind the natural glucocorticoids cortisol and corticosterone with a 10-fold higher affinity than GRs. The glucocorticoids are inactivated only in the nucleus tractus solitarii (NTS), rendering the NTS-localized MRs aldosterone-selective and involved in regulation of salt appetite. Everywhere else in the brain MRs are glucocorticoid-preferring. MR and GR are transcription factors involved in gene regulation but recently were also found to mediate rapid non-genomic actions. Genomic MRs, with a predominant localization in limbic circuits, are important for the threshold and sensitivity of the stress response system. Non-genomic MRs promote appraisal processes, memory retrieval, and selection of coping style. Activation of GRs makes energy substrates available and dampens initial defense reactions. In the brain, GR activation enhances appetitive- and fear-motivated behavior and promotes memory storage of the selected coping style in preparation of the future. Thus, MRs and GRs complement each other in glucocorticoid control of the initiation and termination of the stress response, suggesting that the balance in MR- and GR-mediated actions is crucial for homeostasis and health.
This article addresses the role of the glucocorticoid and mineralocorticoid hormones in the processing of circadian events and stressful information. The glucocorticoids cortisol and corticosterone are the end product of the hypothalamic-pituitary-adrenal (HPA) axis and have a pleiotropic function. The hormones modulate energy metabolism, stress coping, and adaptation with the goal of supporting resilience and health. However, if dysregulated by chronic stressors these very same hormones may promote vulnerability to disease by downregulation of essential defense mechanisms and the choice of counterproductive coping strategies. These actions exerted by glucocorticoids are mediated by two closely related receptors: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). It appears that MRs and GRs coordinate in a complementary manner the action of glucocorticoids during circadian activities (e.g., feeding and sleeping) and in the response to stressors (de Kloet et al., 2018; Joëls, Sarabdjitsingh, & Karst, 2012; McEwen, 2007; McEwen, De Kloet, & Rostene, 1986).
This article concerns the function of MRs and GRs in glucocorticoid regulation of physiological and behavioral adaptations. To better understand MR and GR function, the localization of the receptors is leading in the implication of particular neuronal circuits, while the action mechanism points to recruitment of particular signaling pathways. An important aspect of the MRs and GRs is that these receptors can integrate the genomic and non-genomic action mechanism of glucocorticoids over time domains from seconds to years—and when it concerns programming of brain function, even for life. Another equally important aspect is the conditional nature of glucocorticoid actions, implying that their actions may vary depending on environmental context. Thus, glucocorticoids regulate cognitive processes in hippocampus and prefrontal cortex circuitry, affect emotional responding in the extended amygdala, and drive appetitive and motivational functions in the striatal area (Radley & Johnson, 2018; Ulrich-Lai & Herman, 2009).
In this article, first the properties of MRs and GRs are described as well as how these receptors are implicated in the regulation of the HPA axis. Then the role of MRs and GRs in the regulation of stress coping, behavioral adaptation, and memory storage is reviewed. In the final section the role of the receptors in the organization of brain stress circuitry during development is discussed. It has been shown that these so-called programming effects may predispose an individual to stress-related disorders (McEwen, 2017b; Turecki & Meaney, 2016; Weaver et al., 2004).
The Stress Response
The stress concept coined by Hans Selye in 1936 was defined as the “non-specific response of the body to any demand for change” (Selye, 1936). A stressor is then any stimulus that causes a stress response, which relies on the physiological and behavioral adaptations to maintain homeostasis. Selye demonstrated that chronic exposure to noxious stimuli of any kind always caused a triad of symptoms: stomach ulcer, reduction of thymus weight, and increase of adrenal weight. Very influential was Selye’s general adaptation syndrome concept, in which three stages were distinguished. First was a brief alarm stage lasting minutes, which energizes the individual to immediately deal with the stressor. Second was the stage of resistance, which builds up during chronic stress over days and weeks as the individual continuously mounts defense reactions. The individual adapts to this increasing demand but at a tremendous cost that is indicated as “wear and tear.” Then, finally, exhaustion, when energy resources have become depleted and the flexibility to cope with a new stressor is compromised. As a consequence, adaptation breaks down and vulnerability to disease is enhanced (Selye, 1950).
Selye’s original stress concept has been further developed over the past decades. Thus, it was recognized that stress is not so much what happens but rather how the individual receives it and copes (Lazarus, 1993; Mason, 1971). Accordingly, the “non-specificity” noted by Selye more reflects the secretion of glucocorticoids than it refers to the highly specific pathways processing stressors. Coping strategies and adaptation appeared not to be general but highly individual-specific. Coping with stress can actually be a rewarding experience, which is entirely different from the mostly negative connotation of stress by the public. Psychological stressors, either real or imagined, require processing in higher brain regions and have a strong anticipatory component. These psychogenic stressors should be distinguished from stressors with a primary physical cause that deal with stimuli generated by, e.g., pain, blood loss, and tissue damage, which obviously also have psychological components (Herman et al., 2003). The concept of allostasis was introduced to describe the process of adaptation to change, i.e., to establish a new homeostatic setpoint. In the realm of psychological stressors allostasis relies on anticipation, predictability, and controllability. In fact, uncertainty is one of the most potent psychogenic stressors and illustrates that allostasis describes a labile equilibrium requiring energy. This energy is termed allostatic load (for discussion on the validity of the allostasis concept, see de Kloet, 2016; de Kloet, Ortiz Zacarias, & Meijer, 2017; Koob & Volkow, 2016; McEwen & Wingfield, 2010; Ramsay & Woods, 2014).
If chronic stressors are characterized by a continuous condition of uncertainty, lack of control, and inability to predict, the psychological defense mechanisms and their physiological support require additional energy expenditure. To conceptualize this increased cost, the term “allostatic load” was introduced. This is a stage where adaptation has become very costly. The brain circuitry that serves adaptation by coping with the stressor has become atrophied because of the demand and cannot be used on an ad hoc basis anymore. While healthy organisms are able to bounce back and to regain strength from stressors, the “stressed-out” individual has lost this capacity of “resilience” (Karatsoreos & McEwen, 2011). Then, as predicted by Selye’s general adaptation syndrome, a heterologous stressor can lead to a sudden breakdown of adaptation, simply because brain circuits are not able or equipped to process this novel information. The brain is “locked,” it reverts to emotional overdrive and habitual behaviors, vulnerability to stress-related disorders is enhanced, and disease may precipitate in predisposed individuals (Kwako & Koob, 2017; McEwen et al., 2015; Sousa, 2016). Predisposition depends on interaction between genetic background and previous life experiences. Hence, prior to a certain tipping point preventive strategies, such as a change in lifestyle, assist in sustaining health; beyond the tipping point a disease may become manifest and a curative approach is needed.
Glucocorticoids and Mineralocorticoids
Corticosterone was isolated in 1936 from the adrenal glands and synthethized (de Fremery, Laqueur, Reichstein, Spamhoff, & Uyldert, 1937). The glucocorticoid was immediately linked to the stress response, and in 1938 Dwight Ingle discovered the glucocorticoid feedback control of pituitary adrenocorticotrophic hormone (ACTH) in a classical endocrine experiment. He observed that exogenous cortisol suppressed adrenal weight in intact animals, but not if these animals were hypophysectomized and treated with ACTH (Dallman, 2005). In 1950 Reichstein, Kendall, and Hench received the Nobel Prize for their discovery that cortisol relieves rheumatoid arthritis or, as stated “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.” Ever since, glucocorticoid analogs are commonly used as potent anti-inflammatory and immunosuppressive agents.
The principal glucocorticoid of rodents is corticosterone, while in humans cortisol and corticosterone circulate in a ratio of 20:1. These glucocorticoids are secreted in hourly pulses, which have their largest amplitude at the beginning of the active period in anticipation of energy-demanding daily activities. Ultradian amplitude is smallest at the end of the active period in order to prepare for sleep, and together these hourly pulses form the circadian activity of the HPA axis (Spiga, Walker, Gupta, Terry, & Lightman, 2015). An additional and very important aspect of this ultradian rhythm is that it maintains responsivity of the HPA axis to stress; if the rhythm is flattened, the stress-induced HPA axis response becomes sluggish, implying less efficient coping with threats (Lightman & Conway-Campbell, 2010; Sarabdjitsingh et al., 2010, 2014).
Circadian- and stress-induced HPA axis activity is driven by neural inputs to the paraventricular neurons in the hypothalamus, where corticotropin-releasing hormone (CRH) is synthethized. This peptide is secreted via the nerve terminal in the portal vessel system to stimulate the synthesis of pro-opiomelanocortin, which is cleaved into, e.g., ACTH, which via the circulation stimulates the secretion of the adrenal glucocorticoids. Co-secretagogues, in particular vasopressin, potentiate the CRH action on pituitary corticotrophs. Glucocorticoid feedback on the paraventricular nucleus (PVN) inhibits stress-induced HPA axis activity, as it does in high concentrations on pituitary ACTH. Obviously, since glucocorticoids facilitate behavioral adaptation, higher brain circuits are the main determinant of HPA axis activity (Herman et al., 2003).
Glucocorticoids are synthetized in the mitochondria of the adrenal cortex zona fasciculata. The hormone promotes gluconeogenesis in the liver, proteolysis in muscle, and lipolysis in fat under conditions of high energy demand. The brain has a very high energy demand, and to meet the requirements the glucocorticoids coordinate appetite and food intake with allocation and expenditure of energy by boosting mitochondrial function. Since steroid degradation is regulated by cytochrome P450, the glucocorticoid hormones can be regarded as some kind of “mitokine” (Picard, McEwen, Epel, & Sandi, 2018). Besides allocation of energy, glucocorticoids also promote storage of energy in liver and fat cells at times of recovery and rest. This dual function of glucocorticoids—energy expenditure and storage—is mediated in concert with a host of metabolic factors, which by themselves also have a potent action on the neural circuits and the hypothalamic PVN that regulate HPA axis activity (de Kloet & Herman, 2018; Picard et al., 2018; Weger & Sandi, 2018).
The general action of glucocorticoids during stress has been conceptualized by Marius Tausk and Allan Munck (Munck, Guyre, & Holbrook, 1984; Tausk, 1952) and later by Sapolsky, Romero, and Munck (2000). In this concept glucocorticoids are secreted in order to prevent the primary defense reactions, activated by the stressor, from overshooting and becoming damaging themselves. In 1952 Tausk stated that “cortisone treatment is appropriate where the defensive reactions cause more damage than the agent against which they defend,” while stating metaphorically that glucocorticoids “protect against the water damage caused by the fire brigade” (Tausk, 1952, p. 3; de Kloet et al., 2017, p. 270).
Aldosterone, a naturally occurring mineralocorticoid, is secreted from the adrenal zona glomerulosa under the influence of the renin-angiotensin system. Na+ depletion, reduction in blood volume, and sympathetic nervous activity promote the release of renin from the kidney. Renin cleaves angiotensinogen released from the liver, which is then, via lung angiotensin converting enzyme, further cleaved into angiotensin II, which promotes release of aldosterone. The same enzymes occur also in brain, where angiotensin II is a neuropeptide with a potent influence on drinking while acting in synergy with aldosterone on salt appetite (de Kloet & Joëls, 2017; de Kloet et al., 2017; Krause & Sakai, 2007).
Glucocorticoid Receptors and Mineralocorticoid Receptors
The actions of glucocorticoids and mineralocorticoids are mediated by NR3C1 and NR3C2, which encode GRs and MRs, respectively. These are nuclear receptors that regulate gene transcription. In brain, the first indication of high affinity receptor sites was discovered by Bruce McEwen in 1968 (McEwen, Weiss, & Schwartz, 1968). To his surprise the tracer amount of 3H-corticosterone, administered to adrenalectomized rats, was not retained in the hypophysiotropic hypothalamus but in higher limbic brain regions. Highest retention was observed in the nuclei of hippocampal pyramidal and dentate gyrus neurons, lateral septum, amygdala, and parts of the medial prefrontal cortex. The discovery also raised a conundrum since administration of 3H-dexamethasone, a potent synthetic glucocorticoid, did not match the retention pattern of corticosterone. Rather the tracer doses were retained in high amounts in anterior pituitary and to some extent in the PVN (de Kloet, Wallach, & McEwen, 1975).
Around 1985–1987, MRs and GRs were cloned and the expression of mRNA and protein was examined in brain and pituitary (Evans & Arriza, 1989). It was found that, surprisingly, the neuro-anatomical expression pattern of the MRs, in particular in hippocampus, largely matched the distribution of labeled corticosterone receptors. GRs were found expressed everywhere, with highest density in the anterior pituitary, PVN, limbic-prefrontocortical regions, and ascending aminergic neurons. Meanwhile, we (Reul & de Kloet, 1985) had shown in 1985 that actually there are two populations of corticosterone-binding receptor sites in brain, something we already suspected in the mid-1970s but never really understood how and why. We demonstrated in 1985 the presence of one population in limbic regions that did bind corticosterone with very high affinity and were indicated as type 1 receptors or MRs (because also aldosterone did bind with high affinity). Because of their high affinity, MRs were already substantially occupied at basal circulating corticosterone levels. The other, the classical GRs (or type 2), required circadian peak and stress levels of corticosterone to become activated; GRs were virtually devoid of ligand at low basal corticosterone levels (Reul & de Kloet, 1985). This distinction between MRs and GRs based on localization and binding properties opened a gold mine for new experiments. Yet there were two puzzling questions.
First, why is dexamethasone not retained by brain GRs in tracer amounts, while the synthetic steroid is much more potent and binds with high affinity? This conundrum was resolved in 1995 when it appeared that synthetic glucocorticoids are excellent substrates for multidrug resistance P-glycoprotein. In mutant mice in which MDR1a, the principal gene, was deleted, dexamethasone was retained very well in GR-containing structures in higher brain regions. The same was observed after additional deletion of the MDR1b variant (but not with deletion of MDR1b alone) that was present in much lower amounts. These studies also revealed that, surprisingly, aldosterone and cortisol, but not corticosterone, are substrates for MDR. With this finding the conundrum of the differential corticosterone and dexamethasone retention in the rat brain was resolved, but it had interesting implications. Moreover, because cortisol is a substrate in humans, the corticosterone/cortisol ratio of 0.06 in blood increased to 0.3 in brain, implying that in brain corticosterone accumulates five-fold more than cortisol (Karssen et al., 2001; Meijer et al., 1998; Pariante, 2008).
Second, “mineralocorticoid” receptor suggests an undisputed function in Na homeostasis, and indeed that is what MRs do in epithelial cells of kidney, bladder, and intestines. The gene encoding MRs in brain and kidney is the same. Actually, the limbic MR and also other MRs in non-epithelial cells in heart, fat, and elsewhere appeared promiscuous. The MRs did bind with high affinity cortisol (to be expected), aldosterone (to be expected), and also a range of other steroids such as progesterone and deoxycorticosterone. This might be related to the phylogenetically earlier presence of MR prior to the GRs, progesterone receptors, and androgen receptors but later presence than the estrogen receptors (Baker, Funder, & Kattoula, 2013). But if this is the reason, what is then determining MR specificity in non-epithelial cells and, foremost, the aldosterone-selectivity of epithelial cells involved in Na+ transport?
This conundrum was resolved in 1988 independently by a consortium led by Chris Edwards in Edinburgh and John Funder’s group in Melbourne (Edwards et al., 1988; Funder, Pearce, Smith, & Smith, 1988). It was discovered that 11β-hydroxysteroid dehydrogenase type 2 (HSD2) inactivates cortisol to cortisone and likewise corticosterone to its 11 keto congener in epithelial cells. Because of inactivation of the glucocorticoids, aldosterone can then bind to the MR. In non-epithelial cells (e.g., neurons), the 100- to 1,000-fold excess of the naturally occurring glucocorticoids over aldosterone suggests that these MR rather “see” predominantly cortisol and corticosterone rather than the mineralocorticoid aldosterone. It has been argued that an unfavorable redox climate in the cell may actually favor binding of aldosterone (Funder, 2016), a suggestion that awaits further confirmation.
An additional factor to consider in this line of reasoning is that glucocorticoids rather than aldosterone are bound to corticosteroid binding globulin (CBG), reducing the difference in concentration between free corticosterone/cortisol and aldosterone. However, aldosterone is more rapidly cleared from the circulation and is—like cortisol rather than corticosterone—hampered in brain penetration by the blood-brain barrier. Most important, however, is that glucocorticoids are regenerated in most brain cells by the reductase isoform (HSD1), also in sites involved in glucocorticoid feedback. Activation of 11HSD1 in the PVN therefore increases glucocorticoid feedback and, in higher brain regions, the GR-mediated action on behavioral adaptation (Chapman, Holmes, & Seckl, 2013).
Nevertheless, the presence of aldosterone-selective sites in the brain were long suspected, and circumventricular organs as well as regions in the hypothalamus were indicated as targets (Krause & Sakai, 2007). Indeed, these regions lack a blood-brain barrier and might well be targeted by free aldosterone in high concentration. Moreover, a small group of neurons in the nucleus tractus solitarii (NTS) abundantly expresses HSD2, which thus can ensure aldosterone selectivity of the co-localized MRs. This finding led to the identification of an aldosterone-selective NTS-based neuronal network that innervates the locus coeruleus/parabrachial area, the bed nucleus striae terminalis (BNST), and to a minor extent limbic and ventral striatum regions. This network forms the substrate for aldosterone-driven salt appetite, autonomic outflow that—with the cognitive, emotional, social, arousing, and motivational aspects of salt hunger—is essential for survival in case of lack of salt (Gasparini et al., 2019).
In conclusion, MRs and GRs bind natural glucocorticoids with an order of magnitude difference in affinity and are co-localized. MRs are abundantly expressed in limbic circuits. GRs are widely expressed in neurons and glial cells and have highest expression in brain centers with a prominent function in the control of the physiological and behavioral stress response.
Action Mechanism of Glucocorticoids
For more than half a century it has been known that MRs and GRs are nuclear receptors involved in the regulation of gene expression. Less well known is that these very same receptors also engage in rapid non-genomic actions.
Free circulating glucocorticoids dissociate from the large steroid fraction bound to CBG, enter the cell, and interact with MRs and GRs to produce rapid non-genomic and genomic effects in a time-dependent and coordinated manner. The genomic pathway is initiated by release of several heat shock proteins (HSP), notably HSP90, once the glucocorticoid binds to its receptors. A co-chaperone of HSP90 is FKBP5, which acts in an ultra-short feedback loop: its synthesis is enhanced by GRs, and increased FKBP5 activity desensitizes the GR, causing resistance to glucocorticoid feedback. Gain of function genetic variants of FKBP5 are associated with depression and post-traumatic stress disorder (PTSD), suggesting that receptor turnover should also be taken into account (Conway-Campbell et al., 2007).
MRs and GRs bind to glucocorticoid response elements (GREs) in the DNA. Since the DNA binding of MRs and GRs is 96% identical, they were found to bind almost exclusively as homo- or heterodimers to identical GREs (Mifsud & Reul, 2016; Polman, de Kloet, & Datson, 2013; Pooley et al., 2017; Presman & Hager, 2017). Indeed, GR-dependent effects on hippocampal neuronal excitability and spatial learning were abolished if GR homodimerization was prevented (Karst et al., 2000; Oitzl, Reichardt, Joëls, & de Kloet, 2001; Reichardt et al., 1998). Another interesting feature is that ChIPseq analysis of DNA binding in vivo revealed a population of GREs that bound to GRs only at very high glucocorticoid concentrations (Polman et al., 2013). This observation suggests that GREs also can display differential affinity to MRs and GRs, which is in line with the observation that EC50 values of glucocorticoid-dependent gene induction show large variation (Reddy, Gertz, Crawford, Garabedian, & Myers, 2012). This suggests a mechanism that can differentiate qualitatively between high levels of glucocorticoids because of circadian variation or after exposure to stress (Meijer et al., 2018).
Further ChIPseq analysis revealed in hippocampus a mechanism that enabled differentiation between MRs and GRs to DNA binding sequences. It was discovered that MR binding to GRE was always accompanied by the NeuroD transcription factor (van Weert et al., 2017). In fact, the specificity of glucocorticoid actions mediated by MRs in vivo seem to be conferred by NeuroD allowing the identification of selective MREs. Perhaps also for GRs, specific GRE environments assign specificity rather than involving transrepression via binding to other non-receptor transcription factors such as AP-1 and NF-kB (Meijer et al., 2018). Transrepression refers to in particular GR monomer interaction with other transcription factors such as NF-κB as a mechanism to explain the anti-inflammatory action of glucocorticoids. However, this view was recently disputed with the identification of GR binding to “cryptic” DNA sequences within the genomic NF-κB response elements (κBREs) that mediate GR-driven repression of inflammatory gene expression (Hudson et al., 2018).
Upon binding to DNA the receptors recruit transcriptional coregulators. This group of either co-activators or co-repressors is involved in remodeling of chromatin and the formation of transcription-initiator complexes (Zalachoras et al., 2013). It is thought, similar to transcription factors, that the co-regulators are determinants of the context in which MRs and GRs mediate glucocorticoid action. An example is the Crh gene, which is suppressed by GR-mediated negative feedback in PVN and enhanced in the extended amygdala as part of GR’s control of emotional expression and stress coping (Makino, Gold, & Schulkin, 1994). Hence, there is great interest in the development of selective GR modulators capable to recruit cocktails of coregulators that can affect the action of glucocorticoids in specific cellular contexts (Zalachoras et al., 2013). This would help to better understand the genomic signature of glucocorticoid actions during chronic and acute stress exposure (Datson et al., 2013; Gray, Rubin, Hunter, & McEwen, 2014; Polman et al., 2012). But, foremost, it opens up a possibility to address an urgent medical need for more selective glucocorticoids with fewer side effects.
Although rapid-onset effects of corticosteroids had been described in the 1970s, the fact that both MRs and GRs belong to the family of nuclear receptors, acting through transcriptional regulation, precluded a straightforward explanation of this phenomenon for many years. The field of rapid steroid actions accelerated when in the mid-1990s an orphan G-protein coupled estrogen receptor was cloned, later designated as the G-protein coupled estrogen receptor (GPER); this explained rapid estrogen actions through presumed membrane ERs, including membrane subpopulations of ERα and ERβ. Very similar subpopulations are thought to exist for MR and GR too, although convincing evidence is lacking to date and no separate G-protein coupled molecule has been isolated for corticosteroids in rodents (for review, see Groeneweg, Karst, de Kloet, & Joëls, 2012).
Nevertheless, rapid corticosteroid actions have been increasingly studied and are now generally thought to contribute to the early phase of the stress response, in concert with other stress mediators such as monoamines and CRH. The rapid actions differ, though, between brain areas. For instance, in the PVN rapid suppression of spontaneous glutamatergic transmission was described more than 15 years ago; it appears to involve GRs and retrograde signaling via endocannabinoids (Hill & Tasker, 2012; Jiang, Liu, & Tasker, 2014).
By contrast, corticosterone rapidly and reversibly increases glutamate signaling in hippocampal CA1 and dentate gyrus neurons. Studies with pharmacological tools and genetically modified animals demonstrated that the rapid actions in the hippocampus critically depend on an MR variant that is accessible from the outside of the plasma membrane (Karst et al., 2005). Very similar observations were made in the basolateral amygdala, although MR-induced rapid actions last for more than 1 hour. The rapid actions through membrane-associated MR variants become apparent with corticosteroid doses ~10 times higher than those involved in the genomic pathways (Karst et al., 2010). This suggests that membrane-associated MRs, unlike the nuclear variant, play a minor role when corticosteroid concentrations are low, such as under rest; yet they become active when hormone levels rise, such as after stress or at the peaks of the ultradian pulses, at least in the hippocampus. This lends a new role to the MR as quick “corticosensor” of the brain, in addition to the role of MRs located in the nucleus, which are thought to be important for long-term cellular viability and stability of signals.
Evidence for a role of MRs in the early phase of the stress response has come from behavioral studies, using either MR-antagonists (in humans and rodents) or mice with genetically up- or downregulated MR expression. These studies have shown that immediately after stress or a peak in corticosteroid concentration, MRs strengthen the connection between centromedial amygdala and dorsal striatal circuits, at the expense of connections with, e.g., the hippocampus. This MR-dependent shift promoted the use of proximal versus distal cues in a spatial learning task and was responsible for a shift from trace (hippocampus-dependent) to delay (amygdala-dependent) fear learning (Schwabe, 2017; Vogel et al., 2015, 2017).
The MR:GR Balance Hypothesis
Our research 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 (de Kloet, Vreugdenhil, Oitzl, & Joëls, 1998; Holsboer, 2000). The balance hypothesis is a further elaboration of Selye’s “pendulum hypothesis” in which glucocorticoids and mineralocorticoids were considered to be antagonistic adaptive hormones. A relative excess of mineralocorticoid was thought to increase vulnerability to inflammation, while excess glucocorticoids increased the risk for infection (de Kloet, 2016; de Kloet et al., 2017; Selye, 1950). Accordingly, the balance hypothesis extends Selye’s view of mineralocorticoids versus glucocorticoids to the action of one single hormone, cortisol, which is mediated in a complementary manner by MRs and GRs. The next sections will summarize the progress in testing the MR:GR balance hypothesis on different levels of biological organization from neuronal excitability to behavioral performance.
HPA Axis Regulation
MRs and GRs are co-expressed in limbic structures, but in PVN-CRH neurons and anterior pituitary POMC cells mostly GRs occur. The two receptor types differ an order of magnitude in affinity to cortisol and corticosterone. Based on this difference in affinity and the circulating glucocorticoid levels, this suggests that the MR is concerned mostly with basal control, while the GR only becomes activated after stress and at the circadian peak and is therefore important for negative feedback (de Kloet, 1991, 2014; de Kloet, Joëls, & Holsboer, 2005; de Kloet & Reul, 1987). Of note, this concerns the nuclear MRs; the membrane MRs have a 10-fold lower affinity which allows rapid regulation.
The GR that is expressed in the anterior pituitary POMC cells is the target of stress-induced HPA axis suppression by synthetic glucocorticoids (de Kloet, van der Vies, & de Wied, 1974; de Kloet et al., 1975). This action exerted by dexamethasone is the basis of the dexamethasone suppression test and the combined dexamethasone-CRH test used to assess a potential hyperdrive of HPA axis activation by CRH and vasopressin released in the portal vessels (Holsboer & Ising, 2010). Dexamethasone given (for days to weeks) in low doses poorly penetrates the brain; hence the synthetic glucocorticoid does not target brain feedback sites. Yet, because of its suppression of the HPA axis, the body and brain are depleted of endogenous glucocorticoids. For the brain this results in a relative hypocorticoid state, which is in particular reflected in deficiency of the MR-preferring sites (Karssen, Meijer, Berry, Sanjuan Piñol, & De Kloet, 2005a).
Surprisingly, in adult rats, endogenous corticosterone does not target pituitary ACTH release, except perhaps at extremely high concentrations. This observation was confirmed in the GRPOMCCre mutants that have their GRs selectively deleted during embryogenesis from the anterior pituitary and arcuate nucleus. These mice have increased corticosterone secretion during their postnatal stress hyporesponsive period (SHRP), however (Schmidt et al., 2009). The explanation for this peculiar phenomenon probably lies in CBG. During adult life CBG enters pituitary cells and seems an intracellular reservoir for endogenous corticosterone, which is only exceeded with super-high corticosterone levels (de Kloet, Burbach, & Mulder, 1977). The neonate lacks CBG during early postnatal life, which explains why during this early phase in life the deletion of GR and thus apparently the ability of corticosterone to maintain the SHRP is alleviated.
The PVN is the obvious site of direct glucocorticoid feedback regulation in the brain, and variations in its function were shown to determine the rate in shutoff of stress-induced HPA axis activation. This was demonstrated by local administration of GR antagonists either intracerebroventricularly or directly into the PVN (de Kloet, De Kock, Schild, & Veldhuis, 1988). For site-specific genetic deletion, Sim1Cre-GRe3delta and Sim1Cre-GRe2delta were generated that displayed a partial downregulation of GR expression during embryonic development and early postnatal life. The mutants displayed a normal circadian rhythm but, as expected, showed hyperresponsiveness of the HPA axis (Arnett, Muglia, Laryea, & Muglia, 2016).
Regulation of the HPA axis, however, is in particular dependent on its innervations from higher brain structures, since it can be predicted that when an individual adapts to a stressor, the activation of the HPA axis also cedes. In agreement, forebrain deletion of GR increases basal and peak levels of corticosterone as well as stress-induced HPA axis activity, as is demonstrated in the forebrain GR knockout (FBGRKO) mutants that show a progressive knockout of the receptor during 3 to 6 months of age. GR was also selectively deleted from dopaminergic and dopaminoceptive neurons in the Ventral Tegmental Area (VTA) circuit, as well as the central amygdala and the dorsal raphe neurons, and these mutants showed predominantly behavioral disturbances related to the functions of these aminergic circuits (Arnett, Kolber, Boyle, & Muglia, 2011; Barik et al., 2013).
While these genetic deletions allowed to monitor the effect of long-term manipulation, the administration of GR antagonists revealed remarkable aspects of the acute or repeated blockade across multiple days of the central GR. It was demonstrated that a single 100 ng intracerebroventricular (icv) or 5 ng bilateral intra-dorsal-hippocampal administration of the GR antagonist RU486 attenuated the initial ACTH and corticosterone release, but the release was—as expected—prolonged because of interference with negative feedback. Continuous icv infusion via an Alzet minipump for 5 days of the anti-glucocorticoid RU486 (100 ng/h) increased ACTH release and adrenal weight. This increase in adrenal weight likely accounts for the increased amplitude of the circadian rhythm and the exaggerated stress-induced HPA axis activity (Ratka, Sutanto, Bloemers, & de Kloet, 1989; Van Haarst, Oitzl, & De Kloet, 1997; Van Haarst, Oitzl, Workel, & De Kloet, 1996).
The most remarkable observation was, however, made upon a daily repeated systemic administration of RU486 in a very high dose. A high dose of 200 mg/kg mouse was needed because the synthetic steroid is rapidly cleared from the circulation and poorly penetrates the blood-brain barrier. Following the first RU486 administration the expected long-term increase in ACTH and corticosterone levels was observed that lasted at least 16 hours; at 24 hours after administration the treated animals showed a much larger corticosterone response to a novelty stressor than the controls. However, following subsequent daily administration of RU486 the circadian and stress-induced HPA axis response was abolished. Accordingly, it seems that such a very high dose of the anti-glucocorticoid had “reset” the stress response system. The finding has been demonstrated in different laboratories (Dalm, Karssen, Meijer, Belanoff, & de Kloet, 2018; Wulsin, Herman, & Solomon, 2010).
In conclusion, GR-mediated feedback action occurs in the PVN CRH neurons in concert with actions via inputs from limbic-prefrontal cortex circuits that are involved in processing of psychogenic stressors and are underlying behavioral adaptation. These actions are primarily concerned with termination of the stress-induced HPA axis activation. There are also rapid glucocorticoid feedback effects involving endocannabinoids that probably involve membrane receptors for the steroid (Hill & Tasker, 2012). However, at the same time GR activation increases the activity of the ascending noradrenergic and dopaminergic neurons and the expression of CRH in the central amygdala. As a consequence glucocorticoids enhance motivation and emotional reactions of fear. These actions only become a concern under conditions of chronic stress and negative feedback resistance resulting in elevated circulating glucocorticoid concentrations (Barik et al., 2013; Makino et al., 1995).
Blockade of MR with icv administration of spironolactone increased basal circulating corticosterone levels and enhanced stress-induced activation of the HPA axis rather than interfering with termination of the stress response (Ratka et al., 1989). The finding was reproduced by intrahippocampal administration of the MR antagonist (Oitzl, van Haarst, & de Kloet, 1997). Prolonged icv infusion of 100 ng MR antagonist led to a change in setpoint of the HPA axis, which is characterized by increased adrenal weight. Replacement of ADX animals with low doses of corticosterone, just enough to occupy the MRs, normalized ADX-increased ACTH levels, a finding that can be interpreted in support of the inhibitory influence of limbic MR on basal- and stress-induced HPA activity (Dallman et al., 1989). Also in human studies MR antagonists were found to activate basal and stress-induced HPA activation (Heuser, Deuschle, Weber, Stalla, & Holsboer, 2000).
Further studies showed that increased expression levels of MR correlated inversely with corticosterone levels. The Lewis rat, for instance, has notoriously low circulating levels of corticosterone, making this a suitable animal model for the study of autoimmune diseases. The Lewis rat has high hippocampal MR expression, as does the DBA versus C57 mouse, the short attack latency versus long attack latency mice, and Roman high avoidance versus Roman low avoidance rats. Aging, and in humans depression, are associated with lower brain MR expression and increased HPA axis activity, while treatment with antidepressants increases MR expression and downregulates HPA axis activity. In addition, in human studies genetic variation of the MR corresponded with a different stress-induced activation of the HPA axis activity (de Kloet et al., 2016; de Kloet, de Kloet, de Kloet, & de Kloet, 2019; Oitzl, van Haarst, Sutanto, & de Kloet, 1995; van Eekelen, Rots, Sutanto, & de Kloet, 1992; Veenema, Meijer, De Kloet, Koolhaas, & Bohus, 2003).
MR knockout mice that were generated by embryonal deletion of the MR had—as predicted—elevated CRH expression and increased HPA axis activity (Berger et al., 2006). However, other lines that had MR deleted or overexpressed during the first week of life showed no change in circulating corticosterone levels. Finally, different mouse lines were generated that had forebrain MR (MRhi) overexpression and/or global heterozygous GR deletion (GRlo). The GRlo mice showed increased stress-induced HPA axis activity, which was diminished when combined with MRhi, suggesting that MR and GR interact in control of the neuroendocrine stress response. MRhi perseverated in fear-motivated behavior, which could be predicted from previous studies with animals that had MR highly expressed in the limbic brain. The findings support the MR:GR balance hypothesis (Harris, Holmes, de Kloet, Chapman, & Seckl, 2013).
In conclusion, since nuclear MRs are always largely occupied, these receptors likely are involved in setting the threshold or sensitivity of the stress response system. The non-genomic MR-mediated function is in the initiation rather than the termination of the stress response and may involve membrane receptors as well (Joëls & de Kloet, 2017).
The Dexamethasone Story
Synthetic glucocorticoids and the naturally occurring glucocorticoid of humans, cortisol, poorly penetrate the brain because of MDR1, while corticosterone is not hampered. This conclusion was reached in the mid-1990s, 25 years after the seminal observation of the first author (ERdK) as part of his Dutch PhD thesis and postdoc research at the Rockefeller University with Bruce McEwen. The finding produced the concept of “chemical adrenalectomy” when synthetic glucocorticoids are used therapeutically: the suppression of the HPA axis by dexamethasone leads to adrenal atrophy. While in peripheral tissues the synthetic glucocorticoid can exert its anti-inflammatory and immunosuppressive action, the brain MR is depleted of endogenous glucocorticoids (de Kloet, 2014; Karssen et al., 2005; Meijer & de Kloet, 2017).
Side effects of glucocorticoid therapy may be severe behavioral, cognitive, and emotional disorders (Judd et al., 2014). Accordingly, animal and human experiments were devised with a combination of synthetic glucocorticoids and cortisol or corticosterone. Low-dose dexamethasone administration in rodents produced signs of a brain hypo-corticoid state, which was reflected in a reduced dendritic spine turnover in sensorimotor cortical neurons as well as impaired learning; the deficits were prevented upon refill of MRs with corticosterone co-treatment (Liston & Gan, 2011).
In humans it was demonstrated that brain MR activation improved the deficits in sleep pattern and the dysphoric psychological effects caused by dexamethasone (Born, DeKloet, Wenz, Kern, & Fehm, 1991; Groch, Wilhelm, Lange, & Born, 2013). The most striking outcome was, however, in a multicenter, double-blind, randomized controlled trial with children suffering from acute lymphoblastic leukemia (ALL). About one third of the children had no problems, but another third had clinically important emotional side effects. Cortisol supplementation in doses required for substitution in adrenally deficient patients had a substantially improved outcome for emotional symptoms, conduct, and problems related to stress (Warris et al., 2016).
Stress Coping, Adaptation, and Preparation for the Future
MRs and GRs are expressed in higher brain regions that harbor neuronal circuits underlying cognitive functions, emotional expressions of fear to avoid or to fight threats, and the motivation to acquire rewards or social interaction. Temporal and contextual aspects in the functioning of these circuits are important. A recent review highlighted the shift of resources from circuits involved in processing of salient information to activation of executive functions during coping with a stressor. In their article, the authors combined fMRI analysis of the human brain with molecular, cellular, and behavioral findings gathered from animal experiments (Henckens et al., 2012; Hermans, Henckens, Joëls, & Fernández, 2014). Subsequently, reports appeared of studies that integrated the function of MRs and GRs as a framework for the role of glucocorticoids in coordination of stress coping and behavioral adaptation (Vogel et al., 2017).
Coping With Escapable Stressors
The detection threshold determines how well sensory information can be integrated and perceived. Early reports by Robert Henkin assigned an important role to glucocorticoids in taste and smell, but this work was never followed up (Henkin & Daly, 1968). Yet it can be expected that the glucocorticoid-preferring MRs, analogous to their role in the threshold and sensitivity of the stress response system, have a similar function in perception. What has been demonstrated, however, is an undisputed role of the MR in the alarm phase. Attention and vigilance are enhanced by MR activation, which works in synergy with the sympathetic nervous system. The blood pressure response is enhanced by brain MR stimulation, as is fear and aggression. Blockade of the MR during a first violent encounter has a long-lasting effect on the threshold to elicit aggressive behavior in the future. These actions can be related to genomic and non-genomic control by MRs, and their function is to sustain the alarm reaction launched by neuroendocrine HPA axis and autonomous nervous activity (Cornelisse, Joëls, & Smeets, 2011; Kruk, Haller, Meelis, & de Kloet, 2013; Souza, Dal Bó, De Kloet, Oitzl, & Carobrez, 2014; Van Den Berg, de Kloet, Van Dijken, de Jong, & de Kloet, 1990).
At the same time the novel information is appraised for its significance. Is it really a threat? What will happen next? Did this happen before? How to deal with it? This “appraisal” process has a strong anticipatory component and is driven by retrieval of previous experiences with the goal to support “decision-making and planning.” MR activation promotes “retrieval” of memory by an action in the hippocampus. At the same time, MR activation promotes “emotional responding” in synergy with noradrenaline. These effects concern the non-genomic MR, which rapidly increases glutamate release and enhances excitability (Joëls, Karst, DeRijk, & de Kloet, 2008; Groeneweg, Karst, de Kloet, & Joëls, 2011; Karst, Berger, Erdmann, Schütz, & Joëls, 2010; Karst et al., 2005).
Within this same time domain the appropriate coping style is selected. In 1992 Melly Oitzl discovered that blockade of the MR changes the search strategy of rats in the so-called probe trial of the water maze learning trial (Figure 1). While intact animals perseverate in swimming to the location of the escape route they previously had learned, animals pretreated with MR antagonists immediately changed their strategy to search for an alternative (Oitzl & de Kloet, 1992). Fifteen years later Lars Schwabe and Melly Oitzl convincingly demonstrated the crucial role of MR in rapid selection of coping style using a hole board configuration where the animals could choose between a stimulus (habit) response or spatial (cognitive) strategy. Exposure to a stressor or a corticosterone injection favored habit learning, and this switch could be prevented by MR blockade (Arp et al., 2014; Schwabe, Schächinger, de Kloet, & Oitzl, 2010). MR antagonist treatment blocked the stress-induced switch to habit learning, and processing remained stuck in amygdala-hippocampal connectivity with a worsened performance (Schwabe, 2017). Interesting, female rats did not switch to habit learning but maintained cognitive strategies to cope with stress (ter Horst, Kentrop, de Kloet, & Oitzl, 2013).
The findings were reproduced in humans where MR antagonism favored “declarative (thinking) over non-declarative (doing) learning.” Using fMRI, MR activation was found to promote usage of the amygdala-striatal rather than the amygdala-hippocampal pathway (Schwabe, Tegenthoff, Höffken, & Wolf, 2013). Moreover, carriers of a gain-in-function genetic variant of MR relied more on selection of habit memories during stress coping (Wirz, Reuter, Wacker, Felten, & Schwabe, 2017). This particular MR variant is a haplotype (haplotype 2) based on MR rs5522 and rs2070951, which occurs with a frequency of 41.9%. In different cohorts this haplotype 2 was found associated (in females) with optimism, less rumination, protection against depression, and a better outcome of antidepressant treatment together with a more reactive HPA axis response to psychogenic stressors (de Kloet et al., 2016; Hamstra, de Kloet, Quataert, Jansen, & Van der Does, 2017; Klok et al., 2011; Kumsta, Kliegel, Linden, DeRijk, & de Kloet, 2018).
Coping With Inescapable Stressors
The classical paradigm for a depressed phenotype in animal experiments is learned helplessness, where the animal has learned that escape from adversity is not possible because of lack of control (Maier & Seligman, 1976). In past decades the forced swim test (FST), tail suspension test (TST) and sucrose preference test (SPT) were increasingly used to phenotype rodents. These tests, initially designed to routinely screen antidepressants, were later used (anthropomorphic) to identify “depressed states” in animals that were genetically modified or selected or had gone through a stressful life from birth to adulthood. In the FST, the rodent is placed in a beaker with water for 15 minutes. Initially, the animal struggles, swims, or climbs to escape, but sooner or later every animal will show increasingly bouts of floating until an immobile floating position is acquired (Castagné, Moser, & Porsolt, 2009). Then, the next day the animal is subjected to a retest and immobility time is scored. For mice the immobility times during the initial test were used as score. Unfortunately, over the past two decades immobile behavior has been increasingly labeled without comment as “depression.” However, the immobility response is a “dependent variable of the test situation itself ” and therefore cannot be a model of depression (Castagné, Moser, & Porsolt, 2009). In fact, the FST and TST lack face, predictive, and construct validity. Similarly, sucrose preference could be interpreted as an appetitive response that will by definition be strongly affected by glucocorticoids (de Kloet & Molendijk, 2016; Molendijk & de Kloet, 2015, 2019).
Swimming and floating are actually representing “active and passive” coping styles, respectively, that are evolutionary conserved strategies to optimize the chance of survival. In a psychosocial interaction, active coping is characterized by fight or flight as driven by sympathetic nervous activity. Passive coping or conservation withdrawal is parasympathetically dominated (Henry & Stephens, 1977). Active coping is typical for dominant aggressive animals in their home territory, which is why Koolhaas et al. preferred the term “pro-active” to describe the preparedness in control of their environment. On the other extreme are the “re-active” (passive) animals. Reactive refers to the tendency to be driven in behavior by environmental cues. Hence passive behavior or conservational withdrawal with inescapable stressors is meant as a time out to save energy, to recuperate, and to allow wound healing, while the animal is able to cope with changing environments upon dispersal (de Boer, Buwalda, & Koolhaas, 2017; Koolhaas, de Boer, Coppens, & Buwalda, 2010).
Mouse and rat lines have been selected for active and passive behavior. Examples are the previously mentioned short attack latency (SAL) and long attack latency (LAL) mice that were selected for their aggressive traits (Koolhaas et al., 2010), the Roman high avoidance (RHA) and Roman low avoidance (RLA) based on fear-motivated behavior (Steimer & Driscoll, 2003), and the apomorphine susceptible (APO-SUS) and unsusceptible (APO-UNSUS) animals selected on the basis of their gnawing response to the dopamine agonist apomorphine (Ellenbroek & Cools, 2002). The SAL, RHA, and APO-SUS animals all have in common a high sympathetic nervous tone, low HPA axis activity and circulating corticosterone levels, high dopamine and low serotonin activity, and high MR expression in the brain. Likewise, DBA mice vs C57Bl6 mice show a similar difference in phenotype. During the FST, DBA mice with high limbic MR expression prefer to maintain the active coping strategy by showing profound activation of the amygdala dorsal striatum (DLS) pathway, while the passive coping C57Bl6 have c-fos activation in the hippocampus. Interestingly, there is a strong lateralization with the left DLS showing the most profound c-fos expression (Colelli, Campus, Conversi, Orsini, & Cabib, 2014).
Using optogenetics combined with neuro-anatomical tracing techniques, the pathway underlying passive coping in the “inescapable” TST was recently demonstrated. In this work the GABA-ergic neurons of the anteroventral (av) BNST are an important hub that receives an excitatory input from the prelimbic medial prefrontal cortex (pl-mPFC). The GABA-ergic BNST neurons then project to the PVN and the ventrolateral peri-aquaductal grey (vl-PAG). In the experiments of the Radley laboratory, attenuation of the excitatory pre-limbic mPFC input to the avBNST decreases the inhibitory tone over the PVN-CRH neurons, resulting in activation of the stress-induced HPA axis and sympathetic response. At the same time, the attenuation of the GABA-ergic input to the vl-PAG enhances passive coping (de Kloet et al., 2019; Johnson et al., 2019; Radley & Johnson, 2018).
The authors also investigated the pl-mPFC → avBST → vlPAG circuitry in the “shock probe defensive burying paradigm.” In this paradigm, an electrified probe is inserted in the cage of a rodent. The animal starts to investigate the probe and while doing so receives an electric shock. Rodents may avoid the probe (passive coping) or may bury the probe actively in sawdust (active coping). In contrast to the TST, where active coping sooner or later turns into passive coping with the inescapable stressor, the rats can choose in the shock probe test from two equally effective options (immobility or burying). Optogenetic inhibition of the excitatory input to the avBNST—and thus weakening of inhibitory GABAergic control over the vl-PAG—increased immobility (passive coping); increased immobility was actually confirmed by photo-inhibition in the vl-PAG itself. C-fos activation in the avBST correlated negatively with immobility but not with burying, suggesting that GABA-ergic control of immobility requires a “gating” mechanism rather than depending on switching between an active versus passive coping mechanism in the dorsal and ventral PAG. This work builds on the pioneering research of Bandler and Keay, who previously demonstrated that active coping could be elicited by electrical or chemical stimulation of the dorsolateral or lateral (dl- or l) PAG, while stimulation of the vl-PAG neurons, which are innervated by the BNST GABA-ergic input, was linked directly to passive coping (Keay & Bandler, 2001) (Figure 2). Thus, coping is directed to activate defense mechanisms for protection of the “self,” and activation of the MR promotes attention and vigilance and favors an active, preferentially habitual, coping style.
When the stress reaction develops, the rising cortisol/corticosterone concentrations begin to activate GR. The primary goal of GR in peripheral tissues is to reallocate energy to cells and tissues in need. At the same time GR activation prevents the initial defense mechanisms from overshooting and becoming damaging. As mentioned, this relates to the dampening of pro-inflammatory and pro-immune responses driven by MR. It involves the HPA axis by negative feedback (Sapolsky et al., 2000). It also concerns, at the cellular level, the suppression of MR-mediated enhanced excitability. As examples, GR activation induces the reversal of MR-mediated suppression of the 5HT1A hyperpolarization response and also reverses the MR-dependent enhanced afterhyperpolarization (Joëls & de Kloet, 1990, 1992). In this sense, the GR-mediated mechanism synergizes with the prelimbic and infralimbic neuronal ensembles that are recruited to restrain overactivity of emotional and physiological responding triggered in particular by inescapable stressors.
Activation of GR thus starts recovery from the stressor. At that time “rationalization, contextualization and socialization” are promoted via GR. Rationalization implies enforcing the function of the mPFC in the control of working memory, decision-making, and planning. Contextualization hinges on hippocampal GR (Joëls, Karst, & Sarabdjitsingh, 2018). Emotions rely on GR-mediated activation of CRH in the central amygdala (Makino et al., 1994). Motivation to pursue rewards depends on activation of GR in the VTA-DA circuitry (Piazza & Le Moal, 1996). In this respect social interaction also critically depends on the n. accumbens dopaminergic function activated by glucocorticoids via GR (Weger & Sandi, 2018).
When a stressor cannot be controlled, the mPFC network shifts from initial prelimbic-mPFC connectivity with the dorsomedial striatum toward the infra-limbic-mPFC–dorsolateral striatum connection during the attempts to cope with inescapable stressors. Dopamine turnover in the infralimbic mPFC rises, which corresponds with a decrease in VTA-DA activity and a decreased motivation to pursue rewards, social relationships, and pleasure (Fiore et al., 2015). Under such conditions of chronic uncontrollable stress, GR was found to be downregulated in GABA-ergic interneurons of the mPFC (McKlveen et al., 2013). As a consequence the GR-mediated break on GABA-ergic inhibitory control of the infralimbic mPFC circuitry is thought to fail. This chain of events, then, is postulated to lead, together with stress-induced mPFC degeneration (McEwen & Morrison, 2013; Wellman, 2001), to a diminished excitatory control of il-mPFC over their limbic-midbrain targets including the avBNST (Mcklveen, Myers, & Herman, 2015; McKlveen et al., 2016).
The Jim Herman lab further examined the il-mPFC efferents with optogenetic stimulation and neuroanatomical tracing techniques to identify synaptic terminals, while using c-fos–related antigen to identify target cells activated in avBNST, amygdala, and thalamus and hypothalamus projection regions, but not so much in hippocampus and n. accumbens. This type of approach begins to support the evidence that chronic stress changes recruitment of neuronal cell groups from pl-mPFC to il-mPFC, resulting in an altered innervation pattern of the mPFC “projectome” (Wood et al., 2019).
Preparation for the Future
Glucocorticoids promote via GR the consolidation of memory in animals and humans (Roozendaal & McGaugh, 2011). In rodents, this role of glucocorticoids was demonstrated by administering GR antagonists after the learning trial in the Morris water maze test. Also, GR activation by glucocorticoids was shown to promote fear-motivated behavior if the agonist was given right after the learning trial (Oitzl & de Kloet, 1992). Co-administration with a noradrenergic antagonist prevented this memory-promoting effect of glucocorticoids. Accordingly, glucocorticoids promote memory storage, but their action is enhanced if noradrenergic transmission is promoted or even is dependent on the noradrenaline input from the locus coeruleus (Roozendaal, 2004). A potential mechanistic underpinning was discovered in vitro in tissue slices of the amygdala and involved a metaplastic phenomenon in which glucocorticoids via MRs and GRs and noradrenaline via β-adrenergic receptors cooperate. In basolateral amygdala neurons β-adrenergic activation increases miniature excitatory postsynaptic currents (mEPSCs), which are prolonged in duration by corticosterone, at least with high concentrations of the hormones. This may contribute to a well-known phenomenon, that emotionally loaded experiences are best remembered (Karst & Joëls, 2016) (Figure 3).
Glucocorticoids also promote extinction of fear-motivated behavior. These experiments date back to half a century ago when Bohus et al. demonstrated that if the cue is omitted, glucocorticoids rapidly extinguish active and passive avoidance behavior by an action distinct from HPA axis suppression (Bohus & Lissák, 1968). Using the fear-motivated freezing response as the criterion, it was demonstrated more recently that glucocorticoids rather facilitated the storage of a “contextually re-activated” memory trace if it signaled that the situation was appraised as safe or of no more relevance (Cai, 2006). That glucocorticoids could erase fearful memories by storing new memories in a safe context appeared of clinical significance. Symptoms of PTSD and phobias were reduced after glucocorticoid treatment in exposure-based therapy (de Quervain, Wolf, & Roozendaal, 2019). In high doses glucocorticoids were also effective in prevention in emergency-room settings (de Quervain, Aerni, Schelling, & Roozendaal, 2009). Why some of these studies reported positive effects, even when the steroids were given beyond the context of the fear exposures, is unresolved to date.
In the aforementioned inescapable stressful experience of the FST, the acquired immobility was not stored if GR antagonists were given right after the initial test in the dentate gyrus (de Kloet et al., 1988). It appears that the antagonist interferes in discrete neurons of the dentate gyrus with a corticosterone-induced signaling pathway that activates an epigenetic process affecting the expression of immediate early genes involved in processing the inescapable forced swim stressor (Gutièrrez-Mecinas et al.,2011; Saunderson et al., 2016).
In conclusion, glucocorticoids are involved in different phases of the stress response from coping and adaptation to preparation for the future. These effects are mediated in a complementary manner by MRs and GRs. The MRs control appraisal of salient information and selection of an appropriate coping style, which is stored via GR activation in the memory for future use (Figure 4).
Early Life Stress
In rodents during a two-week SHRP, the circulating corticosterone levels are low. Stressors that would trigger a large corticosterone response at adulthood produce little rise in corticosterone levels during the SHRP. At that time, CBG levels are below detection limits, implying that corticosterone actually circulates as free hormone. Limbic MRs have reached adult levels at the end of the first postnatal week and are, because of their high affinity, occupied by corticosterone. This has led to the conclusion that MRs are involved in maintaining the quiescence of the HPA axis in early rodent life. The most prominent cause of the SHRP is, however, the hypo-responsiveness of the adrenals. Yet the small stress-induced increases in corticosterone during the SHRP are sufficient to activate the GR-mediated pituitary feedback mechanism. This ensures that the SHRP is maintained during exposure to common stressors (de Kloet, Rosenfeld, Van Eekelen, Sutanto, & Levine, 1988; Levine, 2005; Levine, de Kloet, Dent, & Schmidt, 2010; Schmidt et al., 2009).
However, glucocorticoid feedback is overridden when the pup is separated from the dam. After 24 hours of maternal deprivation, corticosterone secretion is high and the HPA axis has become highly responsive to stressors (Schmidt et al., 2003). Responsiveness is suppressed if aspects of maternal care are mimicked (e.g., by feeding and stroking). In the 24-hour deprived animals the PVN c-fos and CRH response and the pituitary ACTH response to stressors are abolished by anogenital stroking of the pups every 8 hours for 45 seconds. If the animals are additionally fed, the deprivation-induced elevated corticosterone and downregulated brain GRs are normalized (van Oers, de Kloet, Whelan, & Levine, 1998). Moreover, further studies showed that feeding and stroking can abolish disruptions of HPA axis reactivity not only during maternal deprivation but also in the long-term. The adult neuroendocrine outcome and behavioral outcome of maternally deprived animals subjected to feeding and stroking early in life was not different from controls. If the elevated corticosterone levels were suppressed during deprivation by dexamethasone treatment, the disruptions in HPA axis regulation remained (van Oers, De Kloet, & Levine, 1999). Dexamethasone treatment during early life also had long-term adverse effects on brain and behavior, which, strikingly, could be abolished by increased maternal care (Claessens, Daskalakis, Oitzl, & de Kloet, 2012).
Other studies showed that the pup’s HPA axis readily habituates to daily repeated maternal separation but continues to respond to stressors (Enthoven, Oitzl, Koning, Van Der Mark, & De Kloet, 2008). It seems therefore that already at postnatal day 5 the pup can predict after one experience that the mother will return at the end of the day; the stress system stays on alert, however. It makes a difference, though, whether the pups during deprivation stayed in a novel environment or remained in the home cage during the 8-hour separation procedure (Daskalakis et al., 2011). When placed in a novel environment, the amygdala c-fos and pituitary ACTH response to stress were enhanced (and corticosterone levels reduced) as compared to animals that had stayed in the home cage. This enhanced stress-induced amygdala and ACTH activation of pups that stayed in a novel rather than a home environment persisted into adulthood and was correlated with enhanced fear-motivated behavior (Daskalakis et al., 2014). During early life the absence of fear-aversion learning is crucial for forming dam–pup attachments. The findings show that disruption of such attachments activates corticosterone action in the amygdala to advance fear aversion learning with long-term consequences for emotional responding (Moriceau, Wilson, Levine, & Sullivan, 2006).
Models and Mechanisms
Based on this principle of mother–pup attachment, several animal models have been used. The classical model is “early handling versus non-handling”: the animal is handled every day for 15 minutes during the SHRP, and upon return the dam engages in intensive licking and grooming of the pup. Such animals display lower stress-induced HPA axis activity and reduced emotional reactivity at adulthood into senescence, which in retrospect likely is due to the more intense maternal care (Levine, 1957; Meaney, Aitken, van Berkel, Bhatnagar, & Sapolsky, 1988). A second model is “maternal separation for prolonged periods versus animal facility rearing,” either for one long period of 24 hours or repeated daily episodes between 1 and 6 hours. The outcome of this approach depends on the duration, frequency, and housing condition during the separation, while the age and sex of the pups are also important variables (Rosenfeld, Suchecki, & Levine, 1992). Other frequently used methods are “communal nesting versus standard nesting” and “limited access to nesting material versus non-handling in normal nesting” (Branchi, 2009; Rice, Sandman, Lenjavi, & Baram, 2008). Then, finally, the model using “naturally occurring variations of maternal care” is based on a comparison between “high and low licking and grooming” of the pups by the dam or a foster mother. The method reveals individual differences depending on maternal behavior (Weaver et al., 2004).
These early life models allowed monitoring of the phenotype of the offspring, which depends on the quality of maternal care, early and peripubertal life conditions, and genetic background. This was particularly well investigated in relation to genetic variations related to the dopamine system. Variations in these three interacting factors (three hits) have led to the finding that severe early adversity or trauma is associated with psychopathology (Daskalakis, Bagot, Parker, Vinkers, & de Kloet, 2013). Three—not mutually exclusive—concepts are pursued:
• The “cumulative stress concept” or the classical stress-diathesis theory, where cumulative stressors eventually pass a certain tipping point beyond which preventive care is not sufficient anymore and curative care is required to treat the stress-induced disorder (Daskalakis et al., 2013).
• The “predictive adaptive (match/mismatch) concept” in which a mild early life stressor is thought to inoculate the animal in preparation for an expected future context. If at later life a mismatch occurs between the programmed phenotypic outcome and the ability to cope with the real challenge, the stress system may become dysregulated, with maladaptive consequences in behavior (Champagne et al., 2008; Hanson & Gluckman, 2014; Nederhof & Schmidt, 2012).
• The “differential susceptibility” theory, which proposes that certain genetic backgrounds make individuals more susceptible for their environment in general, be it beneficial or adverse. This theory also has been popularized as “for-better-and-for-worse” framing of genetic predisposition as vulnerable in one context and resilient in another (Ellis, Boyce, Belsky, Bakermans-Kranenburg, & van Ijzendoorn, 2011). Such differential susceptibility is associated with the gain of function MR haplotype 2 (Endedijk et al., 2019).
A clear example of the match/mismatch is presented in pups that were exposed to high licking and grooming (LG) versus low LG as an index for the quality of maternal care. High maternal care offspring show in later life an attenuated HPA axis response to mild stressors, reduced emotional reactivity, better performance in spatial learning tasks, and a corresponding enhanced long-term potentiation (LTP) response in ex vivo hippocampal slices, a phenotype that was previously found for animals subjected to early handling (Levine, 1957; Meaney et al., 1988). At the morphological level, the high-LG animals show in hippocampus increased dendritic arborizations with proliferated synaptic boutons. MR and GR expression is also much higher in the hippocampus of adult high-LG than in low-LG offspring. However, such well-groomed pups perform poorly at adulthood in stressful learning conditions such as are common in fear-motivated behavior. Interestingly, hippocampal LTP of the high-LG animals deteriorated after a corticosterone challenge of the hippocampal slices, while LTP of the low-LG animals improved (Champagne et al., 2008).
A nice example of the “differential susceptibility” scenario is revealed after 24 hours of maternal deprivation. Healthy aging Brown Norway rats, showing at 32 months of age a survival rate of 90%, were deprived of maternal care at postnatal day 3 and monitored in a transversal and longitudinal study design until senescence. Initially, animals became progressively impaired in spatial hippocampal learning between 3 and 12 months of age. They did not show much difference in HPA axis responsiveness until mid-life, when basal levels were decreased and a profound increase in stress responsiveness of the deprived animals was observed, paralleled by a surge in hippocampal MR expression. At senescence again HPA axis responsiveness and behavioral performance were on average not much different between the deprived and the control groups. However, when each animal’s performance was inspected we noted a dramatic increase in individual variation of the deprived group. While most of the maternally nursed animals were somewhat impaired at senescence in performance of a spatial learning task, this pattern was entirely different in the maternally deprived animals. Most of the deprived animals were “either severely impaired or outstanding performers at the expense of the average performers.” Hippocampal BDNF levels corresponded with behavioral performance (Oitzl, Workel, Fluttert, Frösch, & De Kloet, 2000; Schaaf et al., 2001). Research by Carmen Sandi further investigated if the aging trajectory driven by stress and high MR expression at midlife was linked to a particular genotype. It was observed that animals selected for low reactivity to novelty and high MR expression showed at aging the best cognitive performance following a 4-week chronic stress procedure at midlife (Sandi & Touyarot, 2006).
Most likely, the underlying mechanism of these prolonged influences of early life environment is the epigenetic modification of the genome, i.e., the epigenome. Epigenetic modification does not cause a change in nucleotide sequence but rather affects its functionality in expression by DNA methylation, histone modification, and other mechanisms that produce chromatin reorganization as is the case for the coregulators (Turecki & Meaney, 2016). Other examples are presented by epigenetic modifications of the vasopressin (Murgatroyd & Spengler, 2011), oxytocin (Galbally et al., 2018), and11HSD genes (Wyrwoll & Holmes, 2012). Two decades ago the methylation state of the GR promotor at exon 1F (homologous to human 1F and a locus of NGF1-A transcription factor binding) was found to correlate with maternal care in hippocampus of low- and high-LG rat offspring (Weaver et al., 2004). This would explain the profound differences in GR expression as a function of received maternal care. Moreover, such a mechanism may serve as some kind of “molecular memory” in HPA axis setpoint regulation and brain function (Meaney, Szyf, & Seckl, 2007).
Intriguingly, transmission of these epigenetically modified genes to the next generation was discovered (Bohacek & Mansuy, 2015). In post-mortem human brain, signs of epigenetic signatures were found that corresponded to traumatic early life experiences (McGowan et al., 2009). Epigenetic markers may also be used to predict the outcome of early life experiences as appeared recently from studies in the Western Australian Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) cohort, where epigenetic modifications from placenta and infant buccal cells related to depression and antidepressant use of the mothers predicted mental disorder and dysregulated HPA axis of 12-month-old children (Galbally et al., 2018). An increasing database will enable pinpointing the mechanism underlying mental disorders associated with traumatic early life events.
Reprogramming of the stress system is likely during sensitive periods in life, such as in infancy and during puberty. There is increasing evidence that such programming effects may also be triggered by severe psychogenic stressors in later life (Nasca et al., 2015; Turecki & Meaney, 2016). As genetic substrates for such stress-related reprogramming effects, the mediators of the stress system are indicated, notably the GR in the hippocampus. Even a brief GR activation causes extensive changes in the epigenome (Hunter et al., 2012).
Previously, profound changes in hippocampal excitability had been observed following a glucocorticoid challenge in animals with a history of daily exposure to repeated or variable stressors (Joëls, Karst, Krugers, & Lucassen, 2007; Karst & Joëls, 2003). The analysis of laser-dissected subregions of the hippocampus of such animals showed that 50% of the responsive genes appeared unique and involved in chromatin remodeling, epigenetic processes, and cell adhesion (Datson et al., 2013). Accordingly, GR antagonists have appeared as powerful substances able to reinstate the HPA axis setpoint after disturbance induced by early life adversity (Loi et al., 2017), a stressful puberty (Papilloud et al., 2018), or after stress at adulthood (Dalm et al., 2018). CREB-BP expressed in the hippocampal dentate gyrus may be one of these switches (Datson et al., 2012; Oomen, Mayer, de Kloet, Joëls, & Lucassen, 2007).
In conclusion, an overwhelming database on early life programming has been collected over the last 60 years after Seymour Levine first reported the enduring effects of early handling in rodents. Early life trauma has been indicated as an important risk factor in later life precipitation of mental disorders, particularly related to dopamine, such as depression, addictive disorders, and schizophrenia. In a recent mixed three-level meta-analysis of 1,009 comparisons, Valeria Bonapersona (Bonapersona, Joëls, & Sarabdjitsingh, 2018) identified the most robust changes of dopamine biomarkers in the striatal area. All data are available via the MaDEapp. This app is a useful tool in guiding the design of future research on dopamine, development, and disease.
Geoffrey Harris is considered by many the father of neuroendocrinology because he discovered some 60 years ago (together with Dora Jacobson) that neuronal secretory products of the hypothalamus are in control of pituitary hormone release (Raisman, 2015). Harris passed away before the 1977 Nobel Prize in Physiology or Medicine was awarded jointly to Roger Guillemin and Andrew Schally “for their discoveries concerning the peptide hormone production of the brain” and to Rosalin Yalow “for the development of radio-immuno-assays of peptide hormones” (Rostene & Rostene, 2018). It soon appeared that the pituitary peptides, besides driving hormonal secretions from the endocrine glands, were also produced as precursors for neuropeptides in the brain (de Wied, 1999). Hence, brain-endocrine systems are engaged in control of widely diverse functions in, e.g., reproduction, stress adaptation, energy metabolism, and electrolyte balance. In this connection, Marius Tausk (1902–1980), a famous Dutch endocrinologist, stated on May 10, 1947, on the occasion of the opening symposium of the Netherlands Endocrine Society, that “Endocrinology is a concept, an approach, or even can be considered a method.” Tausk continued, “Whatever the specific endocrine subdiscipline, topic or subject might be, the binding element is the objective, which is the understanding how signals coordinate the processes in cells, tissues and organs.”
This visionary statement of Marius Tausk applies certainly to cortisol and its receptors, which were expected in the hypothalamus but were found surprisingly expressed abundantly in higher brain regions (McEwen et al., 1968). What initially seemed like a single receptor for cortisol appeared soon to be a signaling system with an amazing diversity. First, there were two receptor types, the MR and GR, each encoded by a single gene but occurring in different variants with either gain or loss of function (de Kloet et al., 2018). Moreover, the receptor proteins show more than 10 variants, which can aggregate with dozens of proteins, that additionally show ultra-short autofeedback regulations within this large multimeric cytoplasmic steroid receptor complex. Then there are multiple transcription factors and coregulators that provide hormonal, cellular, and context specificity to the cortisol signal (Meijer et al., 2018; Quinn, Ramamoorthy, & Cidlowski, 2014). On top of that, receptor-activated signaling cascades are capable of integrating non-genomic and genomic actions over time.
MRs and GRs are co-localized but are expressed and regulated differentially and can exert an enormous diversity in action. Yet the function of the glucocorticoids is not so much the regulation of that particular cell group per se but rather its engagement in coordinating the function of spatially widely divergent cells in a temporally and contextually distinct manner. Such a mode of action serves a holistic view of brain, body, and behavior, where the glucocorticoid powers the impact of environmental stressors and modulates the way in which organisms cope. This serves one purpose: to allow the master regulator, cortisol, to promote adaptation in the most efficient manner. Via MR, cortisol or corticosterone can direct stress coping, while via GR the selected strategy is stored in memory for future use. The complementary roles of MR and GR has led to the formulation of the MR:GR balance hypothesis (de Kloet et al., 1998). Further research on these tools of nature may help to identify strategies to prevent the precipitation of stress-related disease characterized by “locked” brain circuits (McEwen, 2017a). Essential for such a strategy is to target mechanisms of plasticity to promote resilience still present in the diseased brain—or as Seymour Levine once said: “nothing is written in stone.”
ERdK gratefully acknowledges support by the Royal Netherlands Academy of Arts and Sciences. MJ is supported by the Consortium on Individual Development (CID), funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant number 024.001.003).
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