Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation.

Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on cognition are complemented by slower actions via glucocorticoid receptors (GRs) on contextualization, rationalization and memory storage of the experience. These sequential phases in cognitive performance depend on synaptic metaplasticity that is regulated by coordinate MR- and GR activation. The receptor activation includes recruitment of coregulators and transcription factors as determinants of context-dependent specificity in steroid action; they can be modulated by genetic variation and (early) experience. Interestingly, inflammatory responses to damage seem to be governed by a similarly balanced MR:GR-mediated action as the initiating, terminating and priming mechanisms involved in stress-adaptation. We conclude with five questions challenging the MR:GR balance hypothesis.

Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid-induced anxiogenic amygdala CRH expression.

Maladaptive glucocorticoid effects contribute to stress-related psychopathology. The glucocorticoid receptor (GR) that mediates many of these effects uses multiple signaling pathways. We have tested the hypothesis that manipulation of downstream factors ('coregulators') can abrogate potentially maladaptive GR-mediated effects on fear-motivated behavior that are linked to corticotropin releasing hormone (CRH). For this purpose the expression ratio of two splice variants of steroid receptor coactivator-1 (SRC-1) was altered via antisense-mediated 'exon-skipping' in the central amygdala of the mouse brain. We observed that a change in splicing towards the repressive isoform SRC-1a strongly reduced glucocorticoid-induced responsiveness of Crh mRNA expression and increased methylation of the Crh promoter. The transcriptional GR target gene Fkbp5 remained responsive to glucocorticoids, indicating gene specificity of the effect. The shift of the SRC-1 splice variants altered glucocorticoid-dependent exploratory behavior and attenuated consolidation of contextual fear memory. In conclusion, our findings demonstrate that manipulation of GR signaling pathways related to the Crh gene can selectively diminish potentially maladaptive effects of glucocorticoids.

Coping with the Forced Swim Stressor: Towards Understanding an Adaptive Mechanism.

In the forced swim test (FST) rodents progressively show increased episodes of immobility if immersed in a beaker with water from where escape is not possible. In this test, a compound qualifies as a potential antidepressant if it prevents or delays the transition to this passive (energy conserving) behavioural style. In the past decade however the switch from active to passive "coping" was used increasingly to describe the phenotype of an animal that has been exposed to a stressful history and/or genetic modification. A PubMed analysis revealed that in a rapidly increasing number of papers (currently more than 2,000) stress-related immobility in the FST is labeled as a depression-like phenotype. In this contribution we will examine the different phases of information processing during coping with the forced swim stressor. For this purpose we focus on the action of corticosterone that is mediated by the closely related mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in the limbic brain. The evidence available suggests a model in which we propose that the limbic MR-mediated response selection operates in complementary fashion with dopaminergic accumbens/prefrontal executive functions to regulate the transition between active and passive coping styles. Upon rescue from the beaker the preferred, mostly passive, coping style is stored in the memory via a GR-dependent action in the hippocampal dentate gyrus. It is concluded that the rodent's behavioural response to a forced swim stressor does not reflect depression. Rather the forced swim experience provides a unique paradigm to investigate the mechanistic underpinning of stress coping and adaptation.

Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior.

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.

Effects of the mineralocorticoid receptor antagonist eplerenone in experimental autoimmune encephalomyelitis.

There is growing evidence indicating that mineralocorticoid receptor (MR) expression influences a wide variety of functions in metabolic and immune response. The present study explored if antagonism of the MR reduces neuroinflammation in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Eplerenone (EPLE) (100 mg/kg dissolved in 30% 2-hydroxypropyl-ß-cyclodextrin) was administered intraperitoneally (i.p.) daily from EAE induction (day 0) until sacrificed on day 17 post-induction. The MR blocker (a) significantly decreased the inflammatory parameters TLR4, MYD88, IL-1ß, and iNOS mRNAs; (b) attenuated HMGB1, NLRP3, TGF-ß mRNAs, microglia, and aquaporin4 immunoreaction without modifying GFAP. Serum IL-1ß was also decreased in the EAE+EPLE group. Moreover, EPLE treatment prevented demyelination and improved clinical signs of EAE mice. Interestingly, MR was decreased and GR remained unchanged in EAE mice while EPLE treatment restored MR expression, suggesting that a dysbalanced MR/GR was associated with the development of neuroinflammation. Our results indicated that MR blockage with EPLE attenuated inflammation-related spinal cord pathology in the EAE mouse model of Multiple Sclerosis, supporting a novel therapeutic approach for immune-related diseases.

Sex differences in fear memory and extinction of mice with forebrain-specific disruption of the mineralocorticoid receptor.

Previous studies showed that the mineralocorticoid receptor (MR) is needed for behavioral flexibility in a fear conditioning paradigm. Female mice with forebrain-specific deletion of the MR gene (MR(CaMKCre) ) were unable to show extinction of contextual fear, and could not discriminate between cue and context fear unlike control mice. In the present study, male and female (MR(CaMKCre) ) mice and control littermates were used to study sex-specific fear conditioning, memory performance and extinction. The fear conditioning paradigm assessed both context- and cue-related fear within one experimental procedure. We observed that at the end of the conditioning all mice acquired the fear-motivated response. During the first minutes of the memory test, both male and female MR(CaMKCre) mice remembered and feared the context more than the control mice. Furthermore, female MR(CaMKCre) mice were not able to extinguish this memory even on the second day of memory testing. The female mutants also could not discriminate between cue (more freezing) and context periods (less freezing). In contrast, male MR(CaMKCre) mice and the controls showed extinction and were capable to discriminate, although the MR(CaMKCre) mice needed more time before they started extinction. These findings further support the relevance of MR for behavioral flexibility and extinction of fear-motivated behavior. In conclusion, the loss of MR in the forebrain results in large differences in emotional and cognitive behaviors between female and male mice, which suggests a role of this receptor in the female prevalence of stress- and anxiety-regulated disorders.

Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioral adaptation.

Corticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the consolidation of memory, the mineralocorticoid receptor (MR) mediates appraisal and initial responses to novelty. Recent findings in humans and mice suggest that under stress, the MR might be involved in the use of different learning strategies. Here, we used male mice lacking the MR in the forebrain (MR(CaMKCre)), which were subjected to 5-10 min acute restraint stress, followed 30 min later by training trials on the circular hole board. Mice had to locate an exit hole using extra- and intra-maze cues. We assessed performance and the use of spatial and stimulus-response strategies. Non-stressed MR(CaMKCre) mice showed delayed learning as compared to control littermates. Prior stress impaired performance in controls, but did not further deteriorate learning in MR(CaMKCre) mice. When stressed, 20-30% of both MR(CaMKCre) and control mice switched from a spatial to a stimulus-response strategy, which rescued performance in MR(CaMKCre) mice. Furthermore, MR(CaMKCre) mice showed increased GR mRNA expression in all CA areas of the hippocampus and an altered basal and stress-induced corticosterone secretion, which supports their role in the modulation of neuroendocrine activity. In conclusion, our data provide evidence for the critical role of MR in the fast formation of spatial memory. In the absence of forebrain MR spatial learning performance was under basal circumstances impaired, while after stress further deterioration of performance was rescued by switching behavior increasingly to a stimulus-response strategy.

Relevance of stress and female sex hormones for emotion and cognition.

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.

A molecular blueprint of gene expression in hippocampal subregions CA1, CA3, and DG is conserved in the brain of the common marmoset.

Recent studies in rodents have shown that there are significant differences in gene expression profiles between the hippocampal subregions CA1, CA3, and DG. These differences in molecular make-up within the hippocampus most likely underlie the differences in morphology, physiology, and vulnerability to insults that exist between the subregions of the hippocampus and are as such part of the basic molecular architecture of the hippocampus. The aim of this study was to investigate at large scale whether these subregional differences in gene expression are conserved in the hippocampus of a nonhuman primate, the common marmoset. This study is very timely, given the recent development of the first marmoset-specific DNA microarray, exclusively containing sequences targeting transcripts derived from the marmoset hippocampus. Hippocampal subregions CA1, CA3, and DG were isolated by laser microdissection and RNA was isolated, amplified, and hybridized to the marmoset-specific microarray (EUMAMA) containing more than 1,500 transcripts expressed in the adult marmoset hippocampus. Large differences in expression were observed in particular between the DG region and both pyramidal subregions. Moreover, the subregion-specific patterns of gene expression showed a remarkable conservation with the rodent brain both in terms of individual genes and degree of differential expression. To our knowledge, this is the first study investigating large scale hippocampal gene expression in a nonhuman primate. The obtained expression profiles not only provide novel data on the expression of more than 1,500 transcripts per hippocampal subregion but also are of potential interest to neuroscientists interested in the role of the different subregions in learning and memory in the nonhuman primate brain.

Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus.

The CA1 pyramidal neurons in the hippocampus contain a high density of adrenal corticosteroid receptors. By intracellular recording, CA1 neurons in slices from adrenalectomized rats have been found to display a markedly reduced afterhyperpolarization (that is, the hyperpolarizing phase after a brief depolarizing current pulse) when compared with their sham controls. No differences were found for other tested membrane properties. Brief exposure of hippocampal slices from adrenalectomized rats to glucocorticoid agonists, 30 to 90 minutes before recording, greatly enhanced the afterhyperpolarization. In addition, glucocorticoids attenuated the norepinephrine-induced blockade of action potential accommodation in CA1 neurons. The findings indicate that glucocorticoids can reduce transmitter-evoked excitability in the hippocampus, presumably via a receptor-mediated genomic action.

Mineralocorticoid receptors in control of emotional arousal and fear memory.

The stress hormone corticosterone acts via two receptor types in the brain: the mineralocorticoid (MR) and the glucocorticoid receptor (GR). Both receptors are involved in processing of stressful events. A disbalance of MR:GR functions is thought to promote stress-related disorders. Here we studied the effect of stress on emotional and cognitive behaviors in mice with forebrain-specific inactivation of the MR gene (MR(CaMKCre), 4 months old; and control littermates). MR(CaMKCre) mice responded to prior stress (5 min of restraint) with higher arousal and less locomotor activity in an exploration task. A fear conditioning paradigm allowed assessing in one experimental procedure both context- and cue-related fear. During conditioning, MR(CaMKCre) mice expressed more cue-related freezing. During memory test, contextual freezing remained potentiated, while control mice distinguished between cue (more freezing) and context episodes (less freezing) in the second memory test. At this time, plasma corticosterone levels of MR(CaMKCre) mice were 40% higher than in controls. We conclude that control of emotional arousal and adaptive behaviors is lost in the absence of forebrain MR, and thus, anxiety-related responses are and remain augmented. We propose that such a disbalance in MR:GR functions in MR(CaMKCre) mice provides the conditions for an animal model for anxiety-related disorders.

[Stress: a neurobiological perspective]. / Stress: neurobiologisch perspectief.

BACKGROUND: Stress is essential for our health and resilience, but vulnerability to psychopathology is increased when the action of a chronic stressor becomes excessive, prolonged or inadequate. METHOD: This survey reviews the literature on the role that the hypothalamic-pituitaryadrenal (hpa) system plays in the neurobiology of stress. Corticotropin-releasing hormone (crh), vasopressin, adrenocorticotropin hormone (acth) and beta-endorphin are very important in the stress reaction. In this paper the focus is on cortisol action in the brain. results Cortisol is secreted by the adrenal cortex in hourly pulses and constantly following stress. The action of cortisol is mediated by binding two types of receptor proteins which influence gene transcription, namely mineralocorticoid receptors (mr) and glucocorticoid receptors (gr). mr and gr are located primarily in the hippocampus, amygdala and prefrontal cortex which regulate emotion and cognition. mr and gr are important for energy metabolism and regulate daily and sleep-related events. During stress, mr in coordination with other signals determines the defense against the stressor, hereas gr assists with the recovery and processing of stressful information and the storage of the experience in the memory. CONCLUSION: Heightened vulnerability to stress-related psychopathology arises when an imbalance occurs between the mr-activating and the gr-suppressing components of the stress reaction. The balance depends on the ability to cope with stress, which in turn depends on genetic factors interacting with the outcome of previous stressful experience.

Nuclear receptor coregulators differentially modulate induction and glucocorticoid receptor-mediated repression of the corticotropin-releasing hormone gene.

Nuclear receptor coregulators are proteins that modulate the transcriptional activity of steroid receptors and may explain cell-specific effects of glucocorticoid receptor action. Based on the uneven distribution of a number of coregulators in CRH-expressing cells in the hypothalamus of the rat brain, we tested the hypothesis that these proteins are involved as mediators in the glucocorticoid-induced repression of the CRH promoter. Therefore, we assessed the role of coregulator proteins on both induction and repression of CRH in the AtT-20 cell line, a model system for CRH repression by glucocorticoids. The steroid receptor coactivator 1a (SRC1a), SRC-1e, nuclear corepressor (N-CoR), and silencing mediator of the retinoid and thyroid hormone receptor (SMRT) were studied in this system. We show that the concentration of glucocorticoid receptor and the type of ligand, i.e. corticosterone or dexamethasone, determines the repression. Furthermore, overexpression of SRC1a, but not SRC1e, increased both efficacy and potency of the glucocorticoid receptor-mediated repression of the forskolin-induced CRH promoter. Unexpectedly, cotransfection of the corepressors N-CoR and SMRT did not affect the corticosterone-dependent repression but resulted in a marked decrease of the forskolin stimulation of the CRH gene. Altogether, our data demonstrate that 1) the concentration of the receptor, 2) the type of ligand, and 3) the coregulator recruited all determine the expression and the repression of the CRH gene. We conclude that modulation of coregulator activity may play a role in the control of the hypothalamus-pituitary-adrenal axis.

Hypothalamic-pituitary-adrenal axis activity of newborn mice rapidly desensitizes to repeated maternal absence but becomes highly responsive to novelty.

In CD1 mice we investigated the hypothalamic-pituitary-adrenal (HPA) axis response to maternal separation for 8 h daily from postnatal d 3 to 5. At d 3 a slow separation-induced corticosterone response developed that peaked after 8 h, and the pups became responsive to stressors. On the second and third day, the response to 8 h separation rapidly attenuated, whereas the response to novelty did not, a pattern reflected by the hypothalamic c-fos mRNA response. If maternal separation and exposure to novelty were combined, then after the third such daily exposure, the sensitivity to the stressor was further enhanced. Meanwhile, basal corticosterone and ACTH levels were persistently suppressed 16 h after pups were reunited with their mothers. To explain the HPA axis desensitization after repeated separation, we found that circulating ghrelin levels increased and glucose levels decreased after all periods of maternal separation, ruling out a role of altered metabolism. Glucocorticoid feedback was not involved either because a glucocorticoid receptor antagonist amplified the corticosterone response after the first but became ineffective after the third separation. In contrast, a mineralocorticoid receptor antagonist decreased and increased corticosterone levels after the first and third period of separation, respectively. In conclusion, the newborn's HPA axis readily desensitizes to repeated daily maternal separation, but continues to respond to novelty in a manner influenced by a central mineralocorticoid receptor- rather than glucocorticoid receptor-mediated mechanism.

Brain corticosteroid receptor balance in health and disease.

In this review, we have described the function of MR and GR in hippocampal neurons. The balance in actions mediated by the two corticosteroid receptor types in these neurons appears critical for neuronal excitability, stress responsiveness, and behavioral adaptation. Dysregulation of this MR/GR balance brings neurons in a vulnerable state with consequences for regulation of the stress response and enhanced vulnerability to disease in genetically predisposed individuals. The following specific inferences can be made on the basis of the currently available facts. 1. Corticosterone binds with high affinity to MRs predominantly localized in limbic brain (hippocampus) and with a 10-fold lower affinity to GRs that are widely distributed in brain. MRs are close to saturated with low basal concentrations of corticosterone, while high corticosterone concentrations during stress occupy both MRs and GRs. 2. The neuronal effects of corticosterone, mediated by MRs and GRs, are long-lasting, site-specific, and conditional. The action depends on cellular context, which is in part determined by other signals that can activate their own transcription factors interacting with MR and GR. These interactions provide an impressive diversity and complexity to corticosteroid modulation of gene expression. 3. Conditions of predominant MR activation, i.e., at the circadian trough at rest, are associated with the maintenance of excitability so that steady excitatory inputs to the hippocampal CA1 area result in considerable excitatory hippocampal output. By contrast, additional GR activation, e.g., after acute stress, generally depresses the CA1 hippocampal output. A similar effect is seen after adrenalectomy, indicating a U-shaped dose-response dependency of these cellular responses after the exposure to corticosterone. 4. Corticosterone through GR blocks the stress-induced HPA activation in hypothalamic CRH neurons and modulates the activity of the excitatory and inhibitory neural inputs to these neurons. Limbic (e.g., hippocampal) MRs mediate the effect of corticosterone on the maintenance of basal HPA activity and are of relevance for the sensitivity or threshold of the central stress response system. How this control occurs is not known, but it probably involves a steady excitatory hippocampal output, which regulates a GABA-ergic inhibitory tone on PVN neurons. Colocalized hippocampal GRs mediate a counteracting (i.e., disinhibitory) influence. Through GRs in ascending aminergic pathways, corticosterone potentiates the effect of stressors and arousal on HPA activation. The functional interaction between these corticosteroid-responsive inputs at the level of the PVN is probably the key to understanding HPA dysregulation associated with stress-related brain disorders. 5. Fine-tuning of HPA regulation occurs through MR- and GR-mediated effects on the processing of information in higher brain structures. Under healthy conditions, hippocampal MRs are involved in processes underlying integration of sensory information, interpretation of environmental information, and execution of appropriate behavioral reactions. Activation of hippocampal GRs facilitates storage of information and promotes elimination of inadequate behavioral responses. These behavioral effects mediated by MR and GR are linked, but how they influence endocrine regulation is not well understood. 6. Dexamethasone preferentially targets the pituitary in the blockade of stress-induced HPA activation. The brain penetration of this synthetic glucocorticoid is hampered by the mdr1a P-glycoprotein in the blood-brain barrier. Administration of moderate amounts of dexamethasone partially depletes the brain of corticosterone, and this has destabilizing consequences for excitability and information processing. 7. The set points of HPA regulation and MR/GR balance are genetically programmed, but can be reset by early life experiences involving mother-infant interaction. 8. (ABSTRACT TRUNCATED)

Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors.

Corticosterone (100 nm) rapidly increases the frequency of miniature excitatory postsynaptic currents in mouse CA1 pyramidal neurons via membrane-located mineralocorticoid receptors (MRs). We now show that a presynaptic ERK1/2 signalling pathway mediates the nongenomic effect, as it was blocked by the MEK inhibitors U0126 (10 microm) and PD098059 (40 microm) and occluded in H-Ras(G12V)-mutant mice with constitutive activation of the ERK1/2 presynaptic pathway. Notably, the increase in mEPSC frequency was not mediated by retrograde signalling through endocannabinoids or nitric oxide, supporting presynaptic localization of the signalling pathway. Unexpectedly, corticosterone was also found to have a direct postsynaptic effect, rapidly decreasing the peak amplitude of I(A) currents. This effect takes place via postsynaptic membrane MRs coupled to a G protein-mediated pathway, as the effect of corticosterone on I(A) was effectively blocked by 0.5 mm GDP-beta-S administered via the recording pipette into the postsynaptic cell. Taken together, these results indicate that membrane MRs mediate rapid, nongenomic effects via pre- as well as postsynaptic pathways. Through these dual pathways, high corticosterone concentrations such as occur after stress could contribute to enhanced CA1 pyramidal excitability.

Strain specific fear behaviour and glucocorticoid response to aversive events: modelling PTSD in mice.

"Pavlovian" fear conditioning in rodents allows studying the formation and extinction of fear memories. Male C57BL/6J but not BALB/c mice showed differential fear memory performance expressed as freezing and scanning behaviour for context and cue. Glucocorticoid stress hormones modulate the processing of fear-related stimuli. The augmented corticosterone response of BALB/c mice to conditioning and testing, therefore, might have contributed to the strain-dependent formation of fear memories. We propose that modulation of extinction processes by glucocorticoids can be relevant in modelling anxiety disorders.

Effects of maternal deprivation of CD1 mice on performance in the water maze and swim stress.

Rat pups subjected to a single 24h maternal deprivation show altered stress responsiveness and cognitive performance in the water maze in adulthood. Here we show in 6-month-old male CD1 mice (deprived 24h at postnatal day 8) an initial impairment in reversal learning: relocating the platform revealed perseverance in search for the former location. Spatial learning, long-term memory and swim-induced corticosterone responses were not affected. We conclude that reduced flexibility is a subtle long-lasting behavioural change induced by maternal deprivation.

Differential development of stress system (re)activity at weaning dependent on time of disruption of maternal care.

Maternal deprivation, a separation of mother and pups for 24 h in the first weeks of life has long-lasting consequences for the glucocorticoid stress system in rats. We examined in male CD1 mice whether the postnatal day (pnd) of deprivation determines the (re)activity of the stress system at weaning under basal and novelty stress conditions. Maternal deprivation was only effective when applied within the stress hypo-responsive period (SHRP) between pnds 1 and 12, but not on pnd 13. Maternal deprivation (i) early in the SHRP (pnd 3) resulted in lower hippocampal GR mRNA expression together with a prolonged corticosterone response to stress; while (ii) late in the SHRP (pnd 8) the amplitude of the ACTH response to stress was enhanced. (iii) Strikingly, the effects of the double deprivation (pnds 3 and 8) were not additive: sustained, stress non-responsive high plasma ACTH concentrations with corticosterone indistinguishable from control animals coincided with a lower expression of hippocampal MR and GR mRNA. These results present species-specific effects (mouse versus rat) of an adverse early life event on HPA axis regulation at weaning. A subsequent deprivation experience interferes with the effects of earlier deprivation. We conclude that the developmental stage of the organism determines the vulnerability for the detrimental effects of maternal deprivation and the organization of the stress system in adolescence.

Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers.

Glucocorticoids are secreted from the adrenal gland in very high amounts after stress. In the brain, these stress hormones potently modulate ionic currents, monoaminergic transmission, synaptic plasticity and cellular viability, most notably in the hippocampus where corticosteroid receptors are highly enriched. Here we show that at least some of these actions require DNA binding of glucocorticoid receptor (GR) homodimers.