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Adrenal corticosteroid secretion usually reaches maximal levels within 15 min after HPA activation; the adrenal response to ACTH is modulated by locally produced factors and sympathetic nervous activity Corticosteroid hormones feed back in two modes of operation: a proactive MR mode maintaining basal HPA activity and a reactive GR mode facilitating recovery from stress-induced activation.

In concert with other components of the stress response system, the action of corticosterone displays two modes of operation. A brief period of controllable stress may be experienced with excitement and can be beneficial to emotion and health. In contrast, lack of control and uncertainty can produce a chronic state of distress, which is believed to enhance vulnerability to disease.

Corticosterone restrains defense reactions to stress, which would themselves become damaging if left uncontrolled 2 — 4 , and redirects metabolism to meet the energy demands during stress 5. This situation changed when it appeared that the receptors for mineralocorticoids showed high affinity for corticosterone as well as for aldosterone 7 — 9.

Corticosterone actions in the brain are mediated by glucocorticoid receptors GRs and mineralocorticoid receptors MRs 10 , GRs occur everywhere in the brain but are most abundant in hypothalamic CRH neurons and pituitary corticotropes. Aldosterone-selective MRs resembling those in the kidney are expressed at hypothalamic sites involved in the regulation of salt appetite and autonomic outflow 12 — 17 , but these effects are beyond the scope of the present review.

By far, the highest MR expression is found, however, outside the hypothalamus, i. Importantly, in the hippocampus the aldosterone selectivity of MR is lost. Thus, in the hippocampus, one compound, corticosterone, serves to activate two signaling pathways via MR and GR 9. The progressive activation of MRs with a low concentration of corticosterone and additional GR activation when steroid levels rise can cause profound changes in neuronal integrity 21 — 23 and neuronal function 24 associated with changes in neuroendocrine regulation 25 , 26 and behavior In the present review, we will focus on the function of the various types of brain corticosteroid receptors.

Valuable information has been gleaned from a number of recent reviews and books 25 , 26 , 31 — Here we will highlight the determinants of brain corticosteroid receptor activity and examine the various levels at which their function may change. The molecular and cellular responses mediated by, in particular, hippocampal corticosteroid receptors will be considered in the context of HPA regulation and associated behavioral responses.

The thesis is pursued that MRs are involved in maintenance of stress system activity, while GRs in coordination with MRs mediate steroid control of recovery from stress. Also, new findings on the MR-GR interplay are discussed that either challenge or support the original thesis. Further understanding of the role of corticosteroids in gene-environment interactions may help to answer a fundamental question in the endocrinology of stress and disease: when do corticosteroid hormone actions cease to be beneficial to health and, instead, become damaging?

When corticosteroid hormones enter the brain compartment, they bind to intracellular receptors. The corticosteroid receptors are part of a cytoplasmic multiprotein complex, which consists of one receptor molecule and several heat shock proteins hsp [ i. Binding of glucocorticoids leads to a rapid chain of events consisting of dissociation of the hsp and immunophilin, multiple phosphorylation steps, and increased affinity of the ligand-activated receptor for nuclear domains 49 , Molecular and biochemical studies have demonstrated two receptor subtypes, MR and GR, in brain tissue.

If colocalized, they mediate the corticosteroid signal in synergism or antagonism, depending on cellular context. Several determinants for the receptor-mediated steroid response have been recognized. First of all, the access of synthetic corticosteroids to the brain receptors is determined by a variety of factors, such as corticosteroid-binding globulin CBG , steroid-metabolizing enzymes, and the mdr1A P-glycoprotein.

Second, the responsiveness to corticosteroids is governed by the cellular expression of MR, GR, and their variants. Generation of such variants may be disease-specific, a notion that can now be directly tested in mutant mice carrying a genetic defect in MR or GR. Third, the cellular context and physiological conditions can determine whether the steroid receptor complex either enhances or represses gene transcription. Finally, there may be a higher order control of receptor interaction with the genome, relating to the spatial organization of the cell nucleus during cellular differentiation and growth 51 — 54 ; the latter, however, is beyond the scope of the present review.

Thirty years ago McEwen and co-workers 18 demonstrated that a[ 3 H]corticosterone tracer administered to adrenalectomized ADX rats is retained in high amounts in the hippocampus several hours later: autoradiography showed abundant[ 3 H]corticosterone-labeled cell nuclei in the dentate gyrus and pyramidal cells of the hippocampus as well as in other regions of the limbic forebrain, e.

This retention pattern in limbic brain has subsequently been found in widely divergent species such as birds, dogs, and monkeys that secrete either corticosterone birds, rodents or cortisol dogs, primates as the naturally occurring glucocorticoid. This suggests that the retention of corticosteroids, particularly in the hippocampus, is a trait that is conserved in evolution The early studies with tracer amounts of corticosterone had, in fact, identified MRs rather than GRs in hippocampus, since the tracer dose of corticosterone was too low to detect GR 9 , This became apparent when binding properties of MRs and GRs were studied in cytosol, using selective GR ligands RU that allowed discrimination between the two receptor types 57 Table 1.

Subsequently, it was shown that low basal corticosterone levels predominantly occupy MR. GR can be activated additionally to MR only when corticosterone levels are high, i. With autoradiography of selectively labeled MR and GR 59 , immunocytochemistry 60 — 65 , and in situ hybridization 66 — 69 , the spatial distribution of the two receptor types in brain tissue was studied. In agreement with[ 3 H]corticosterone labeling, MRs prevail in limbic brain areas, while GRs are widely distributed in neurons and glial cells.

Table 2 summarizes in chronological order the highlights in the discovery of brain corticosteroid receptor diversity. The subcellular localization of MR and GR was studied in hippocampal neurons by dual labeling immunocytochemistry and confocal microscopy It was observed that MR and GR are nonhomogeneously distributed over the nucleus.

Both receptors are concentrated in about clusters scattered throughout the nucleoplasm. It was found that many clusters exclusively contain either MR or GR, although a significant number of domains was found to contain both receptor types Fig. The latter clusters are obvious candidate sites at which the two receptors could interact to establish a coordinated regulation of gene expression.

However, we also observed that the distribution of GR clusters in nuclei of human bladder carcinoma cells is not related to transcription initiation sites, suggesting that most of the detected clustered receptor molecules are not directly involved in gene transcription 71 , Colocalization of MR and GR in nuclear domains of hippocampus. Representative confocal microscopy image restored of the distribution of corticosteroid receptor types in the cell nucleus of a rat hippocampal CA1 neuron.

Each cluster is about 10 receptor molecules. Yellow indicates colocalized MR and GR. Single optical sections of three-dimensional images are shown Access of natural and synthetic corticosteroids to brain steroid receptors is controlled by many factors, three of which will be discussed below. The first determinant of corticosterone access to brain is CBG. This amount is in the range of the K d for the corticosteroid receptors, measured in vitro in cytosol. CBG levels are regulated by numerous signals.

Particularly potent inducers of CBG synthesis are the estrogens; this accounts for the much higher level of total circulating corticosterone in females compared with males Glucocorticoids and stress down-regulate CBG CBG is a static regulator of the biological availability of corticosterone. The binding protein is also expressed intracellularly in the pituitary. Here, CBG may compete with the steroid receptor for intracellular corticosterone, as was also found in the liver, kidney, and lung.

In the pituitary, uptake of corticosterone in nuclei of corticotropes is very low, whereas the potent synthetic glucocorticoid dexamethasone does not bind to CBG and is retained in high amounts 19 , Accordingly, CBG is a substrate for neutrophil elastase, which cleaves CBG so that delivery of corticosterone to inflammation targets may be locally enhanced Although CBG is not present in the healthy brain, the latter process may play a role in disease.

The second determinant of corticosterone access to the brain discussed here is a dynamic regulator. In vitro , in hippocampal homogenates, predominantly oxidase activity has been demonstrated, leading several groups to argue in favor of a protective role of this enzyme against corticosteroid overexposure. A third determinant of access, which particularly pertains to synthetic corticosteroids, is the mdr1a P-glycoprotein This protein is expressed in the apical membranes of endothelial cells of the blood-brain barrier Mdr1a P-glycoprotein functions as an energy-dependent pump that limits access to the brain of xenobiotic agents including the synthetic steroids.

Mutant mice with a genetic disruption of the mdr1a gene show increased accumulation of[ 3 H]dexa-methasone in the brain This uptake was found to be further enhanced in GR-containing brain targets for glucocorticoids using autoradiography of brain sections obtained from ADX mutant mice treated with tracer amounts of dexamethasone.

In the hippocampus and PVN of mutant mice, an increase in cell nuclear retention of up to fold was observed, compared with wild-type controls, reaching levels observed in the pituitary 91 , Accordingly, the brain is resistant to penetration of moderate amounts of dexamethasone because of mdr1a P-glycoprotein activity Fig. Since the synthetic steroids are substrates for the P-glycoprotein extrusion pump, they could potentially induce expression of the mdr1a gene and, thereby, enhance their own resistance.

Mdr1a-P-glycoprotein and dexamethasone uptake in brain. Penetration of [ 3 H]dexamethasone was measured at 1 h after administration to these mice, which were adrenalectomized the day before 91 , The human GR is localized on chromosome 5 whereas the MR is localized on chromosome 4, indicating an early duplication of their common ancestor during evolution.

Genomic organization and splice products of the MR and GR genes. Exons are numbered and indicated in boxes. A glucocorticoid responsive element GRE is present in the MR gene as well as the MR splice variant containing 12 additional nucleotides see arrow. Dotted exons 3 and 4 correspond to the DNA-binding domain. Expression of the human MR gene may result in the formation of at least four transcripts, which are derived from two different promoters 94 , , Recently, another intriguing splice variant has been described : the use of an alternative splice site between exon 3 and 4 creates a bp insertion which, after translation, corresponds to four additional amino acids in the amino acid sequence bridging the two zinc finger domains of the DNA-binding domain.

Vreugdenhil, unpublished results. Given the involvement of the DNA-binding domain in translocation of MRs to the nucleus, dimerization, and interaction with other transcription factors, it is very likely that this splice variant will exhibit aberrant functional properties.

As the different splice variants result in the same MR protein, the biological significance of their presence is unclear. Receptor variants may play an important role in the disease state. Thus, individuals with familial glucocorticoid resistance may express a GR variant, and as a consequence have deficient GR function and impaired glucocorticoid feedback resulting in hypercorticoidism. The symptomatology of familial glucocorticoid resistance is usually related to overproduction of adrenal mineralocorticoids and androgens in response to ACTH Although in man these severe inherited deficits in GRs resulting in asymptomatic hypercorticoidism are rare disorders, there are also pronounced species differences in GR, c.

Apparently, the elevated set point in HPA regulation is an adequate adaptation. Ligand-activated GR and MR can contribute to the regulation of gene transcription in at least three different ways Fig. For a detailed overview, see the recent article by Beato and Sanchez-Pacheco Molecular mechanism of corticosteroid action on gene expression.

Corticosteroids cort bind to the GR or MR, which are translocated to the nucleus as dimers. After homodimerization of the GR or MR, the receptors will bind to specific DNA elements, the hormone-responsive elements HRE in promoter regions thereby affecting the transcription rate of corticosteroid-responsive genes. As these motifs are also present in other nuclear receptors, heterodimerization may not be restricted to MR and GR. The first mode involves activation or repression of gene expression through binding of steroid receptors to single, multiple, or composite GREs that are present in the promoter region of glucocorticoid-responsive genes Transcription-initiation by RNA polymerase II also requires interaction of the receptors with docking proteins and with other transcription factors However, the synergizing effect of multiple GREs with GR-activated transcription is not observed with MR activation, probably due to the limited homology of the N-terminal sequences , This involves protein-protein interactions, and dimerization of GRs may not be required The target genes involved lack of GREs.

Dissociation between MR- and GR-mediated events may arise through this mechanism, since it has been shown that GR suppresses AP-1 activity under conditions in which MR is ineffective The third type of interaction concerns the formation of heterodimers between different nuclear receptors.

Along the same lines, several recent papers have reported an inhibitory effect of other nuclear receptors on MR- and GR-mediated action, but the underlying mechanism is still unclear Inadequate repression by GR, which is characteristic of steroid resistance, will alter the functional outcome of such cross-talk.

Alternatively, steroid resistance or supersensitivity can also develop when steroid receptor properties change through enzymatic modifications, e. In the hippocampus, corticosterone binds with a fold higher affinity to MRs than to GRs.

The high affinity MRs, even at basal levels of HPA axis activity, are substantially occupied, suggesting that this receptor is implicated in the maintenance of basal activity of the stress system by proactive feedback. High concentrations of corticosteroids progressively saturate GRs, implying that the suppression of stress-induced HPA activity occurs, in particular, through GRs by reactive feedback in a coordinated manner with MRs.

Consequently, the balance in these MR- and GR-mediated effects on the stress system is of critical importance to the set point of HPA activity. MR and GR activation depends among other things on the access of the hormone to its receptors. Access of the synthetic glucocorticoid dexamethasone to central targets is hampered by mdr1a P-glycoprotein, at the level of the endothelial cells of the blood-brain barrier.

The local generation of MR and GR variants that may interact, and other events in the receptor life cycle, further adds to the modulation of corticosteroid action. MR- and GR-mediated actions occur through activation or repression of gene transcription.

The actions depend on the cellular context, which is determined in part by other agents e. Through membrane-signaling cascades, these can activate their own transcription factors, which in turn interact with MR and GR. The multiple interactions at the DNA and the protein-protein level provide an enormous diversity and complexity of transcriptional control by corticosteroid hormones.

Resistance or supersensitivity of the receptors may be acquired when the receptor interactions become disproportionate. Activation of intracellular corticosteroid receptors in neurons may induce a variety of cellular responses, influencing diverse processes such as cellular structure, energy metabolism, or signal transduction.

Changes in cellular structure usually develop over the course of several days, whereas effects on energy metabolism or signal transduction may become apparent within hours Although the delayed onset of the observed effects, as opposed to the rapidly induced effects by neurosteroids — , favors a gene-mediated effect via MR and GR, the molecular mechanism has, in many cases, not been resolved.

The cellular effects of steroids will have consequences for functional processes involving the hippocampus, e. Steroid effects on cell function can develop with fluctuations of the steroid level within the physiological range, as may occur after acute stress. The nature of these actions may alter when animals are chronically exposed to aberrant corticosteroid levels, e. A conspicious feature of corticosteroid actions on cellular activity in the hippocampus is the apparent lack of effect when neurons are studied under basal conditions: resting membrane potential and membrane resistance do not show steroid dependence — Only when neurons are shifted from their basal condition, e.

This indicates that as for peripheral actions of corticosteroids, their cellular effects in the brain are also aimed at restoring homeostasis. The conductances that are a potential target for steroids can be subdivided into two categories Fig. First, the voltage-gated and ion-sensitive ionic conductances, which are in many cases only indirectly altered by neurotransmitters.

The second category involves the ion conductances, which are directly affected by neurotransmitter actions, either because the channels are an intrinsic part of the transmitter receptors or because the channels are modulated via receptor-activated G proteins. Steroid effects on these two targets will be discussed briefly.

Gene-mediated steroid effects on membrane properties. Changes in transcriptional activity induced by steroid receptor dimers can affect many conductances in neuronal membranes. Targets that are discussed in the text comprise the voltage-gated ion channels, ionotropic receptors, and channels that are regulated via G protein-coupled receptors. It has been shown that the predominant occupation of MRs in CA1 hippocampal neurons is associated with small, voltage-gated Ca currents Fig.

Recent experiments with mice lacking the GR protein through a genetic defect suggest that the presence of at least some functional GRs is required for the MR-mediated reduction in Ca currents to develop When GRs are activated to a large extent, Ca current amplitude increases considerably , The GR-mediated increase in Ca influx depends on de novo protein synthesis Not only voltage-gated Ca influx is affected by corticosteroid receptor occupation: both basal and stimulus-induced intracellular Ca levels were found to be increased by substantial GR activation, which may be explained by steroid effects on Ca buffering or extrusion mechanisms — Corticosteroids and neuronal excitability: implication of U-shaped dose response for hippocampal output.

Properties that determine the cellular excitability in hippocampal cells are differently affected by specific corticosteroid receptor activation. The upper traces show calcium currents evoked in hippocampal CA1 neurons by depolarization of the membrane.

The middle traces illustrate the number of action potentials induced in a hippocampal CA1 neuron during a steady depolarizing input. Due to activation of a calcium-dependent potassium conductance, neurons cease firing after an initial burst of action potentials accommodation. The lower traces show the hyperpolarization of the membrane after activation of serotonin-1a receptors application during horizontal bar. Calcium currents, accommodation, and serotonin responses are large both in the absence of corticosteroids ADX and when MRs and GRs are concomittantly activated.

By contrast, these cell properties are small with a predominant MR activation, pointing to a U-shaped dose dependency. Due to these effects on CA1 excitability, hippocampal output is expected to be maintained at a relatively high tone with the predominant MR activation and reduced when GRs in addition to MRs are activated.

Steroid modulation of Ca homeostasis will have consequences for Ca-dependent phenomena in hippocampal neurons, e. This current hyperpolarizes neurons when they receive a prolonged excitatory input, resulting in a reduction of firing accommodation. Since deactivation of the current is very slow, a lingering afterhyperpolarization AHP can be seen at the end of the depolarization, which also serves to suppress transmission of excitatory input. In accordance with the steroid effects on Ca influx through voltage-gated channels, both the accommodation and AHP amplitude were found to be small with predominant MR activation Ref.

This corticosteroid modulation of the AHP characteristics depends on de novo protein synthesis For a steady excitatory input to the hippocampal CA1 area, this steroid modulation means that the CA1 hippocampal output is effectively transmitted with predominant MR activation and reduced when GRs are concomitantly activated. Other K conductances were found to be far less sensitive to central corticosteroid effects , with only the inwardly rectifying Q current being sensitive to corticosteroid exposure, in a similar way as the Ca currents.

The functional significance of this may be that GR activation counteracts profound perturbations of the membrane potential in the hyperpolarizing direction, i. Similar to the K conductances, voltage-dependent Na conductances were also little affected by steroid receptor occupation Only small shifts in voltage dependency and kinetic properties were observed after adrenalectomy and subsequent steroid receptor occupation.

Still, these small shifts may contribute to an MR-mediated increase in the amplitude and duration of the action potential in CA1 neurons and to an enhanced threshold for the generation of action potentials with concomitant GR activation Although K and Na conductances are thus much less of a target for steroid modulation, MR-mediated effects on these conductances will still promote maintenance of excitatory hippocampal output to other brain regions, while additional GR effects will reduce the hippocampal output.

The predominant signaling molecule in the hippocampal CA1 area is the excitatory amino acid glutamate Several studies have demonstrated modulatory effects of corticosteroids on the amino acid-mediated synaptic transmission. When synaptic responses are recorded extracellularly, predominant MR activation is associated with a stable excitatory transmission at a high tone — Occupation of GRs resulted, usually within 20 min, in depression of the glutamatergic transmission — , particularly with high extracellular Ca concentrations Intracellularly, similar effects were found on excitatory postsynaptic potentials Fast inhibitory postsynaptic potentials are mediated via GABA a receptors Slow inhibitory postsynaptic potentials, mediated via GABA b receptors, are more susceptible to steroid effects These slow inhibitory potentials remain very stable when mainly MRs are occupied, and with additional GR activation they are largely suppressed.

The overall picture is that both excitatory and inhibitory information is maintained at a stable level when MRs are predominantly activated, i. When corticosteroid levels rise and GRs become occupied additionally, excitatory transmission, and thus CA1 hippocampal output, is reduced; at very high steroid levels, inhibitory networks are also impaired. Instead, there is some evidence that the GR effects may involve impairment of energy metabolism , , , which, through failure of electrogenic pumps, could result in a gradual rundown of synaptic responsiveness.

Molecular studies have indeed supplied evidence that GRs affect the expression of metabolic enzymes and other proteins involved in neuronal energy metabolism, e. The high efficiency of amino acid transmission with predominant MR activation is also reflected in long-term plastic changes involving this hippocampal network, i.

In this paradigm, brief tetanic stimulation of glutamatergic afferents to the CA1 area results in enhanced synaptic responses for at least 1 h The prolonged enhancement of synaptic strength is considered to be a neuronal substrate for learning and memory formation. It appeared in both corticosterone-replaced ADX animals and intact rats that synaptic potentiation is most pronounced with moderate corticosterone levels, so that most of the MRs and only part of the GRs are activated , ; when corticosterone levels are either reduced or enhanced synaptic potentiation is far less effective — Similar steroid dependency was observed for synaptic potentiation in other parts of the hippocampal formation, i.

Long-term depression of synaptic responses, which is induced by lower frequency stimulation of glutamatergic afferents, was found to display a similar steroid receptor dependency The observed steroid receptor dependency will have consequences for the efficacy of synaptic potentiation during acute stress.

Thus, it has been shown that exposure to a novelty stress always blocks long-term potentiation , This was also observed after subjecting rats to an inescapable shock, but here stress-induced factors other than corticosterone seem to be involved — In addition to amino acid input, hippocampal neurons also receive considerable input mediated by biogenic amines such as acetylcholine, noradrenaline, and serotonin.

Selective MR activation has not yet been studied. Serotonin 5-hydroxytryptamine, 5HT evokes many different effects in CA1 hippocampal neurons, of which 5HT 1A -receptor-mediated hyperpolarization of the membrane is most prominent This hyperpolarization is small in amplitude with predominant but not exclusive MR occupation Refs. This was seen when corticosterone was applied exogenously and after acute stress The strong inhibitory effect of 5HT with GR activation was shown to result in a marked suppression of the excitatory transmission in the CA1 area MR-mediated reduction of the 5HT response requires de novo protein synthesis Although under comparable conditions, 5HT 1A receptor mRNA expression and binding capacity in CA1 and dentate cells was also reduced , it has not been established that the functional impairment is indeed caused by a reduced binding capacity.

The observation that high corticosterone levels largely suppress 5HT 1A receptor mRNA expression, while responses to 5HT are relatively large, in fact suggests that the changes in mRNA expression may not correlate with the altered responses after steroid treatment.

Acetylcholine affects hippocampal cell properties in many different ways Postsynaptically among others depolarization of the membrane due to blockade of at least two K conductances can be observed. Presynaptically, a large reduction of neurotransmitter release is evoked.

It was observed that the postsynaptic depolarization induced by the metabolically stable cholinergic analog carbachol CCh is small with predominant MR activation Additional GR activation by exogenous corticosterone application, but not after acute stress, resulted in large CCh responses The relevance of this modulation for the CA1 hippocampal excitability is, however, probably rather limited: the consequence of the CCh-evoked depolarization seems to be entirely overriden by the large, steroid-insensitive depression of synaptic responses due to presynaptic cholinergic actions Structural changes of hippocampal neurons were observed both with chronic absence and chronic overexposure to corticosteroids 37 , indicating that steroid-dependent expression of genes is of crucial importance for hippocampal integrity.

Removal of the adrenal glands results, within 3 days, in apoptotic-like degeneration of mature, granule cells in the rat dentatus gyrus, but not in other hippocampal fields. Dentate cells showed chromatin condensation, cell nuclear pyknosis, DNA fragmentation, and cytoplasmic shrinkage , The loss of functional neurons is likely to affect neurotransmission in this and connected regions.

In agreement, it was recently observed that particularly glutamate-dependent features of the synaptic field responses are reduced in animals showing signs of apoptosis The degeneration and associated loss of synaptic function could be prevented by treatment with MR ligands , , Some, but not all , , papers describe a lack of effect of the synthetic glucocorticoid dexamethasone on adrenalectomy-induced apoptosis , , suggesting a controversial role for GRs.

In fact, dexamethasone was found rather to induce apoptosis , because it depletes the brain of corticosterone, creating a condition of chemical adrenalectomy. A different regulation may take place in the neonatal rat , when MR and GR are still developing and conditions, such as maternal separation, actually induce glucocorticoid resistance and apoptosis in the developing hippocampus Several studies have addressed the process underlying the apoptotic-like degeneration after adrenalectomy.

Of paramount importance for one line of investigation is the fact that the dentate gyrus, in contrast to most brain regions, shows neurogenesis even during adulthood , , which can be blocked by chronic stress and adrenal steroids 23 , It was argued that MR activation maintains the balance between cell birth and cell death in the dentate gyrus, by enhancing the excitatory input to this region Adrenalectomy results in increased cell birth and cell death, which is suppressed by corticosterone replacement.

However, newborn neurons in the dentate gyrus do not express corticosteroid receptors, suggesting that the steroid effects on neurogenesis are indirect and possibly involve modulation of excitatory transmission 23 , and neurotrophins , Immediate early genes and cell cycle-related genes, such as the tumor suppressor p53, have been indicated as markers for the cell death cascade after adrenalectomy In vitro experiments show that p53 down-regulates the apoptosis blocker bcl-2 and up-regulates apoptosis enhancer bax by a direct interaction with DNA elements in the promotor region of both genes , , suggesting that adrenalectomy-induced apoptosis is regulated by members of the bcl-2 family.

The expression of a limited number of genes induced by excitatory amino acids was found recently to be enhanced by adrenalectomy One of these genes was identified as the growth-associated immediate early gene Krox Preliminary data indicate increased Krox expression in apoptotic cells in the dentate gyrus, suggesting its implication in control of hippocampal cell viability Although apoptotic neurons were never encountered in the CA1 hippocampal region, cellular function in this region was nevertheless affected by chronic absence of corticosteroids.

The most prominent effect seems to be that voltage-gated Ca currents display a very large amplitude , Interestingly, the Ca-dependent K conductance was rather small in tissue from untreated ADX rats, notwithstanding the large Ca influx Refs. This shows that control of the Ca-dependent K conductance can take place independently of Ca influx, e. Consistent with the latter it was shown that adrenalectomy results in an improved energy supply to CA1 hippocampal neurons Amino acid-mediated transmission in the CA1 hippocampal area was found to be only slightly reduced in tissue from ADX animals , , , , although one study reported a large suppression of field responses Synaptic potentiation in the CA1 area was significantly impaired, however, in ADX rats compared with animals with predominant MR occupation , Changes in GABA-ergic transmission by adrenalectomy seem to be limited Aminergic responses were all relatively large in tissue from ADX rats.

Responses to 5HT were enhanced in tissue from untreated ADX rats, compared with animals with predominant MR activation , , Finally, depolarizing responses to CCh were also larger in tissue from ADX rats than in cells from rats with predominant MR occupation , The data demonstrate that specific parts of the hippocampus, i. Other parts, such as the CA1 area, show little effect on low frequency amino acid-mediated synaptic flow, although long-lasting synaptic changes are also impaired in this region, with profound changes in Ca-conductances and aminergic efficacy.

Functional processes in the hippocampus, such as learning and memory formation, for which long-term modulation of amino acid-mediated transmission and cellular viability are important, are thus likely to be influenced by these cellular effects of adrenalectomy. There is now ample evidence that chronic elevation of corticosteroid levels leads to neurodegeneration or suppressed neurogenesis in the hippocampus 22 , 23 , CA3 pyramidal neurons seem to be particularly vulnerable, although effects in the CA1 and dentate subfield have also been reported Three weeks of restraint stress in rats causes regression of apical dendrites of hippocampal CA3 pyramidal neurons , This effect is mimicked by 3 weeks of treatment with a high dose of corticosterone , and does not occur when corticosterone secretion is blocked by cyanoketone treatment.

The regression occurring after 3 weeks of high levels of corticosteroid is reversible and can be prevented by treatment with the antiepileptic drug, pheny-toin ; an N -methyl- d -aspartate antagonist was also protective Changes in nuclear chromatin structure in CA3 neurons were observed in subordinate tree shrews after a prolonged psychosocial conflict 23 , These data support the view that an imbalance in the CA3 and possibly CA1 network favoring excitatory over inhibitory signals, leading indirectly to enhanced Ca influx, contributes to the observed degeneration.

This is partly supported by the cellular and molecular processes seen under these conditions. Indeed, one of the most prominent features seen with temporary elevations in corticosteroid level, and thus GR occupation, is the long-term enhancement of Ca influx in CA1 neurons , This effect may persist when animals receive very high corticosterone amounts: chronic treatment of ADX rats with a very high corticosterone dose was associated with elevated mRNA levels for several Ca channel subunits By contrast, chronic supply of low levels of corticosterone led to reduced expression.

Experimental work indicates that altered glutamatergic transmission, possibly in combination with enhanced Ca influx, may play a role in neurodegeneration with chronic exposure to high corticosterone levels In agreement, the gene for glutamine synthetase GS , an ATP-requiring enzyme catalyzing the formation of glutamine from glutamate and ammonia, has been shown to contain a GRE.

With chronic elevation of corticosterone levels, the GS gene is markedly activated , , resulting in a depletion of glutamate necessary to maintain or induce synaptic transmission. Moreover, chronic steroid-mediated overinduction of GS and other ATP-requiring enzymes, such as glycerolphosphate dehydrogenase , may deplete ATP stores.

ATP depletion would negatively affect the many ATP-demanding processes that include enzymatic processing, e. It should be noted, however, that basal responses in the CA1 area to synaptic glutamatergic input were largely unaffected in chronically stressed middle-aged rats Nevertheless, a clear reduction of synaptic potentiation due to tetanic stimuli was observed after repeated or chronic 68 exposure to stress.

Lack of neurotrophic capacity may also contribute to enhanced neuronal vulnerability. Indeed, chronic stress or administration of glucocorticoids decreased steady-state levels of the brain-derived neurotrophic factor mRNA — in the dentate gyrus and CA3 layer. Tyrosine kinase B expression also seems to be down-regulated via GR , , while MR activation results rather in an up-regulation of tyrosine kinase B In addition to brain-derived neurotrophic factor, nerve growth factor, basal fibroblast growth factor, and transforming growth factor expression in the hippocampus are also affected by glucocorticoids , , GR activation also facilitates synthesis of glycoprotein neural cell adhesion molecules, which are thought to be necessary to achieve synaptic connectivity underlying storage of information A critical duration of overexposure to steroids is essential for the neurodegenerative effects to develop: temporary high levels of the hormone decrease responsiveness to excitatory amino acids and reduce excitability by activation of Ca-dependent K conductances.

Local depolarization is sustained and breakdown of inhibitory networks occurs due to chronically enhanced corticosteroid exposure. Hippocampal neurons will subsequently be subjected to a substantial GR-dependent rise in intracellular Ca levels. After this line of reasoning, beneficial effects exerted by phasic activation of GRs are turned into damaging actions when GRs are chronically activated. The experiments of Krugers et al. Although neurodegenerative processes are an important feature of chronic overexposure to steroids in the hippocampus, this is by no means the only effect on local signal transduction.

It was observed recently that 5HT-evoked responses in CA1 hippocampal cells, which showed no signs of degeneration, were modulated by chronic overexposure to corticosteroids in a manner that was completely different from the modulation observed with acute rises in corticosterone level , This may signify that the susceptibility of neurotransmitter systems to the actions of corticosterone is altered after long-term treatment with the hormones, or even that chronically elevated steroid levels affect transmitter responsiveness via an entirely different mechanism of action than seen with brief exposure.

Studies at the cellular level have supplied ample evidence that shifts in corticosteroid receptor occupation, such as occur after an acute stress or due to circadian variations in steroid level, exert a delayed and long-lasting control over excitability in limbic brain regions. They do so in a context-dependent manner, i. The interdependency of steroid and neurotransmitter actions fits very well with a molecular mechanism depending on protein-protein interactions rather than one acting via steroid receptor dimers binding to a hormone-responsive element.

Clearly, validation of this idea awaits further electrophysiological studies in animals with genetically modified steroid receptors, such that only one of these molecular mechanisms of action can develop. The general picture emerging is that conditions of predominant MR activation, i. In contrast, additional GR activation, e.

A similar effect is seen after adrenalectomy, indicating a U-shaped dose-response dependency of these cellular responses to corticosteroids. In many cases, the molecular mechanism underlying these cellular effects is not known. For some transmitters the actions seem to involve at least the capacity of the receptor In other cases, second messenger systems may be regulated , , similar to the corticosteroid action observed in pituitary cells In addition to these postsynaptic effects, brief changes in neurotransmitter release may also contribute to the observed depressed activity with acute stress.

The MR- and GR-mediated effects at the cellular and network level will have consequences for functional processes in which the hippocampal formation plays an essential role, e. However, the steroid actions on hippocampal output will also affect, via transsynaptic inhibitory connections with the PVN, neuroendocrine regulation.

Based on the generalization outlined above, predominant hippocampal MR activation will inhibit PVN function, while additional GR activation in these same hippocampal cells is expected to disinhibit feedback function in the PVN. Chronically aberrant corticosteroid levels will not only affect hippocampal cell responses but, in fact, compromise the viability of the cells, particularly when the neuroendocrine dysfunction is associated with additional challenges to the network 29 , 35 , 37 , , Disturbed Ca homeostasis and altered glutamatergic transmission may underlie the observed increased vulnerability.

This implies that when corticosteroid levels are chronically too low or too high, hippocampal transmission is impaired and therefore hippocampal outflow is reduced. It is not known when and how the corticosteroid hormones cease to be beneficial and begin instead to enhance vulnerability to damage. Changes in network function of higher brain areas through molecular and cellular effects of corticosteroids will, via trans-synaptic pathways, result in an altered drive to the hypothalamic CRH-producing neurons.

Moreover, the steroid-induced influences on information processing of the hippocampus may also result in adaptation of behavioral patterns, which indirectly affects the state of the HPA system. These corticosteroid-mediated effects on hippocampus function and their role in the central stress response will be the focus of this section.

As a preamble, regulation by corticosteroid hormones of the stress response directly at the level of the PVN will be briefly summarized. The final part of the section will focus on dysregulation of the HPA system when converging inputs on the CRH neurons either fail to restrain the neuronal activation by stress or prevent it from responding adequately.

Pituitary corticotropes and PVN contain the primary feedback sites for stress levels of the naturally occurring glucocorticoid. At low concentrations of circulating corticosterone, the brain is the primary target — , as access of corticosterone to the pituitary POMC gene is hampered by competitive binding to intracellular CBG-like molecules 19 , 76 , While corticosterone readily enters the brain, the exogenous synthetic glucocorticoids penetrate the brain poorly, reflecting the mdr1a P-glycoprotein barrier 90 — Steroids such as dexamethasone, therefore, predominantly block stress-induced HPA activity at the pituitary level 19 , 92 , , and deplete the brain of exogenous corticosterone.

Three experimental approaches, which have been used to explore the brain feedback sites of corticosteroids, will now be reviewed: 1 replacement of ADX rats with receptor agonists, 2 pharmacological inhibition of individual receptor types in adrenally intact animals using more or less selective antagonists, and 3 correlative evidence between receptor properties and HPA dynamics. In the latter approach, receptor levels were often manipulated with subsequent measurement of the effect on HPA regulation.

Basal ACTH levels are dramatically elevated, while circadian changes and stress responses of the hormone show a large amplitude in excursions Levels of — n m corticosterone, occupying both receptor types and achieved with subcutaneous corticosterone implants, efficiently suppress VP and CRH expression and release into portal blood — Implants of naturally occurring and synthetic glucocorticoids near the PVN act similarly — , while local application of the antagonist RU has the opposite effect The rise in basal trough levels of ACTH after adrenalectomy is prevented by chronic replacement with very low amounts of exogenous corticosterone; under these conditions, corticosterone also suppresses the adrenalectomy-induced synthesis of VP, while CRH is not affected by either treatment The IC 50 of corticosterone suppression is about 0.

Accordingly, MR mediates the proactive feedback mode of corticosterone involved in maintenance of basal HPA activity. At the circadian peak, much higher levels of exogenous corticosteroids are required, and half-maximal suppression is achieved by a free concentration of about 5 n m , close to the K d of GRs 9.

However, exclusive activation of GRs is insufficient to suppress the circadian peak, and MR activation appears to be indispensable The corticosteroid concentration does not need to be continuously high, in that an episodic rise in glucocorticoid levels by injection or ingestion via the normal evening drink is sufficient to occupy both receptor types and to maintain ACTH levels with small amplitude changes over the h period These GR-mediated effects observed after exogenous glucocorticoids thus are also involved in maintenance of HPA activity.

An interesting paradox is that exogenous corticosteroids suppress subsequent stress-induced ACTH levels whereas similar levels of the steroid attained after a first stress do not Apparently, stress evokes in the PVN a local transient condition of steroid resistance; the elevated corticosterone facilitates the termination of the HPA response to stress, and various temporal fast and slow feedback domains have been distinguished These GR-mediated effects triggered in response to stress represent the reactive mode of feedback operation.

Observations on HPA regulation have often been made without consideration of the steroid effects on higher brain functions involved in arousal and processing of information. GR-mediated effects in brain areas projecting to the PVN have profound and long-lasting consequences for feedback regulation.

First of all, ascending aminergic neurons via direct, monosynaptic inputs excite the PVN, an action potentiated by stress and corticosteroids 60 , , Second, the suprachiasmatic nucleus SCN conveys excitatory and inhibitory circadian pacemaker activity to the PVN and other hypothalamic nuclei, an activity that is modulated by corticosteroids.

One such SCN output regulates, via spinal projections, pronounced daily shifts in adrenal sensitivity and corticosterone secretion , These systems with inputs to the PVN generally express GRs and contain numerous colocalized neuropeptides, which also regulate PVN activity in their own right — Moreover, these inputs can be either excitatory from hippocampus, enhancing GABA-ergic tone, or inhibitory e. Roles for the amygdala in fear, anxiety, and activation of HPA axis are well-documented — The amygdala expresses CRH, part of an extrahypothalamic CRH network mediating the behavioral expressions of stress, fear, and anxiety Corticosteroids enhance the expression of CRH in this extrahypothalamic network, suggesting a positive feedback as opposed to the negative feedback role in the hypothalamic PVN.

In contrast, the significance of MR and GR in regulation of CRH expression and function in the amygdaloid nuclei has not been well established. Neuronal afferents, corticosteroid receptors, and HPA control. The diagram shows the organization of the HPA axis and in simplified form, some of its major neuronal afferents. Neural activation of PVN neurons in response to visceral stimuli occurs via monosynaptic catecholaminergic projections arising from brain stem nuclei Projections of the suprachiasmatic nucleus transfer excitatory as well as inhibitory information to ensure circadian rhythmicity of the HPA axis This inhibitory GABA-ergic tone is enhanced by excitatory hippocampal output.

GABA-ergic inhibitory tone is inhibited and thus becomes excitatory through a GABA input from the central amygdala 40 , , , In addition, peptidergic pathways such as neurotensin , neuropeptide Y, opioids and substance P, as well as cytokines, modulate CRH activity Most of these transmitter and peptide projections are transsynaptic, providing ample opportunity for modification of information transfer to the PVN MRs mediate potentiation of hippocampal output, and thus enhance neural inhibition of HPA axis, while via GRs corticosteroids dampen hippocampal output, which thus leads to HPA disinhibition.

The activation of a particular afferent neuronal network innervating the PVN area is stressor specific and depends on the nature of the stimulus — If it constitutes a direct threat to survival through physical stressors e. If sensory stimuli are subject to appraisal and interpretation processing in higher brain regions is required, this may subsequently lead to modulation of GABA-ergic tone and change in synthesis of CRH, VP, and other neuropeptides of the PVN secretagogue cocktail.

Activation of brain stem and limbic circuitry is not separated but, in fact, mutually interactive and stress-induced corticosteroids readily enter the brain and feed back on all components of the neural stress circuitry, but in a context-dependent manner. Lesioning and electrical stimulation studies suggest an overall inhibitory influence of the hippocampus on HPA activity We have based our analysis of hippocampal function on the central administration of selective receptor antagonists in adrenally intact animals, allowing us to study the role of endogenous corticosterone in the presence of adrenal medullary hormones, which have potent actions on brain CRH expression and adrenal sensitivity to ACTH.

In these studies ACTH and free corticosterone levels were measured in sequential blood samples obtained via indwelling intravenous cannulae from freely moving animals. Intraventricular icv administration of MR antagonist elevated basal morning trough levels of plasma corticosterone , and exposure of the rats treated with the antimineralocorticoid to a novel situation resulted in enhanced adrenocortical responses. In the afternoon phase, MR antagonists ng icv also elevated basal ACTH and corticosterone levels , as did a fold lower dose injected bilaterally into the hippocampus Consistent with the MR specificity of the response, a corticosterone implant in the dorsal hippocampus suppressed adrenalectomy-induced elevations in ACTH levels, while dexamethasone implants were ineffective Finally, systemic administration of spironolactone increased basal HPA activity in man , , although this response was not noted in all studies Thus, hippocampal MRs appear to mediate the effect of corticosterone in maintaining the tone of basal HPA activity.

First, the cyclical increase of HPA activity in female rats on the evening of proestrus occurs when the high estrogen and progesterone levels impair MR function; estrogens lower hippocampal MR mRNA levels and binding capacity, while progesterone causes a profound decrease in MR binding affinity Second, rat strains with high levels of hippocampal MR expression e.

Fourth, tricyclic antidepressants increase expression of hippocampal MRs and decrease basal and stress-induced HPA activity 32 , — , also in man Finally, icv administered endotoxin impairs MR function and causes a chronically elevated basal HPA activity This effect of corticosterone via MRs is modulated by GRs that become progressively occupied after stress and during the circadian rise in glucocorticoid, which also negatively feed back on the PVN.

We have found that icv administration of the antiglucocorticoid RU ng to intact rats has no effect on basal morning trough levels of plasma corticosterone, probably because at that time the low levels of corticosterone produce negligible GR occupation 86 , If the antagonist is administered icv during the afternoon phase, basal HPA activity increases, as seen after local administration of 5 ng RU near the PVN.

In contrast, administration of the same dose of antagonist directly into the hippocampus decreased basal ACTH levels in the afternoon phase We interpret these apparent paradoxical data after icv and intrahippocampal administration as follows. First, if solely hippocampal GRs are blocked, their attenuating effect on MR-mediated action is eliminated, resulting in an enhanced MR-mediated inhibitory tone.

Second, if RU is given icv, the effect of blockade at the level of the PVN appears to override that of GR antagonism in the hippocampus. It would be of interest to test this interpretation at the cellular and circuit level. Such opposite effects correlate well with the electrophysiological data previously discussed, since MRs and GRs mediate opposite effects on excitability and excitatory outflow 24 , The nature of the HPA regulation via hippocampal MRs and GRs is also consistent with the cellular actions they evoke in the hippocampus: predominant MR activation comparable with local antiglucocorticoid application maintains hippocampal excitability, and through transsynaptic inhibitory projections to the PVN basal HPA activity.

Conversely, with rising glucocorticoid concentrations, GR activation suppresses the hippocampal output, resulting in a disinhibition of PVN neurons. The functions mediated by both receptor types are linked. A deficiency in MR is predicted to allow more readily a corticosterone response, thus leading to more pronounced GR-mediated effects. While the action of corticosteroid in hippocampus is thus involved in HPA regulation, further fine tuning of the HPA response to stress occurs by its behavioral effect.

The hormone does not necessarily cause a behavioral change, but rather influences information processing and thereby affects the likelihood that a particular stimulus elicits an appropriate behavioral response. Moreover, through coordinate MR- and GR-mediated actions in higher brain areas, e. Accordingly, when the effect of corticosteroid on information processing and cognitive function facilitates behavioral adaptation coping to stress, the associated HPA response is more readily extinguished.

Therefore, when one studies the modulation of behavioral responses by corticosteroids, the time and duration of the hormone action, as well as its context, need to be considered. Stress hormones, including corticosterone, are released during learning and are necessary for establishment of an enduring memory.

In this context the role of corticosteroid hormones on acquisition, consolidation, and retrieval of information has been studied for more than four decades. For this purpose, simple associative learning tasks i. All these tests revealed that administration of exogenous corticosterone in the appropriate temporal context, i. Recently, Sandi and co-workers showed that corticosterone facilitates spatial memory if given immediately after the task in amounts comparable to those elicited by stress.

If, however, an acute stressor is introduced into a training sequence, giving rise to additional hormonal stress responses, spatial learning is impaired These findings emphasize that corticosterone modulates information processing in a time- and context-dependent way. Furthermore, corticosterone administered after training facilitates extinction of passive and active avoidance responses. This implies that in addition to facilitation of learning and memory processes, the steroid also promotes the elimination of behavior that is of no more relevance We now know that these effects of corticosteroids require GR activation.

Adrenalectomy impairs behavioral performance, and replacement with corticosteroids allows identification of not only GR-, but also MR-, mediated responses. A few studies have found a stringent specificity for corticosterone, while dexamethasone and aldosterone were not active.

In the latter test, a complete extinction of an avoidance response is achieved after rats are allowed, shortly after the learning trial, to explore the compartment where they had previously experienced punishment. The response was impaired after adrenalectomy, but maintained exclusively by replacement with corticosterone An interaction of corticosterone with adrenaline was reported by Borrell et al. In all instances, low amounts of corticosterone were given that would lead to predominant occupation of MR.

Moreover, treatment with MR antagonists revealed a change in behavioral reactivity , and this finding further supports the role of MR in processes of selective attention and sensory integration. The importance of the balanced activation of MR- and GR-mediated effects by glucocorticoids on cognitive processes was demonstrated by the use of receptor-specific antagonists Fig. Memory in spatial and avoidance tasks is impaired in the absence of appropriate GR activation after the learning task 27 , , — Moreover, direct injection of a GR antagonist or GR antisense into the hippocampus prevented the retention of immobility in the Porsolt model ,

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Veterinary steroids suppliers Neuroscience 62 : — For a steady excitatory input to the hippocampal CA1 area, this steroid modulation means that the CA1 hippocampal output is effectively transmitted with predominant MR activation and reduced when GRs are concomitantly activated. If coping with stress fails, an imbalance between drive and feedback develops at the level of the PVN, resulting in altered expression of CRH, VP, and other ACTH secretagogues, with the extent of the alterations being dependent on the nature and context of the stress While corticosterone readily enters the brain, the exogenous synthetic glucocorticoids penetrate the brain poorly, reflecting the mdr1a P-glycoprotein barrier 90 — Postsynaptically among others depolarization of the membrane due to blockade of at least two K conductances can be observed.
Organon sustanon 250 steroids for dogs Most of these transmitter and peptide projections are transsynaptic, providing ample opportunity for modification of information transfer to the PVN We have found that icv administration of the antiglucocorticoid RU ng to intact rats has no effect on basal morning trough levels of plasma corticosterone, probably because at that time the low levels of corticosterone produce negligible GR occupation 86 Although in man these severe inherited deficits in GRs resulting in asymptomatic hypercorticoidism are rare disorders, there are also stealth gear steroids review species differences in GR, c. Synaptic potentiation in the CA1 area was significantly impaired, however, in ADX rats compared with animals with predominant MR occupation Moreover, reactive feedback mediated by GR was deficient and further impaired after maternal deprivation. Sustanon for 6 weeks, sustanon otzivi — Buy legal anabolic steroids Sustanon for 6 weeks However, users may still experience high estrogen-like side effects, due to deca raising progesterone; which can stimulate breast tissue in the mammary glands.
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