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Review

Corticosteroid receptors and neuroplasticity

Nuno Sousaa,⁎, João J. Cerqueiraa, Osborne F.X. Almeidab

aLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, PortugalbMax Planck Institute of Psychiatry, Munich, Germany

A R T I C L E I N F O

⁎ Corresponding author. Escola de Ciências da+351 253 604 809.

E-mail address: njcsousa@ecsaude.uminh

0165-0173/$ ­ see front matter © 2007 Elsevidoi:10.1016/j.brainresrev.2007.06.007

A B S T R A C T

Article history:Accepted 22 May 2007Available online 17 July 2007

The balance in actionsmediated bymineralocorticoid (MR) and glucocorticoid (GR) receptorsin certain regions of the brain, predominantly in the limbic system, appears critical forneuronal activity, stress responsiveness, and behavioral programming and adaptation.Alterations in theMR/GR balance appear tomake nervous tissue vulnerable to damage; suchdamage can have adverse effects on the regulation of the stress response and may increasethe risk for psychopathology. Besides the hippocampal formation, other subpopulations ofneurons in extra-hippocampal brain areas have been also shown recently to be sensitive tochanges in the corticosteroidmilieu. From a critical analysis of the available data, the picturethat emerges is that the balance (or imbalance) between MR/GR activation influences notonly cell birth and death, but also other forms of neuroplasticity. MR occupation appears topromote pro-survival actions, while exclusive GR activation favors neurodegeneration.Interestingly, the sustained co-activation of both receptors, for example in chronic stressconditions, usually results in less drastic effects, restricted to dendritic atrophy and impairedsynaptic plasticity. As our knowledge of the plastic changes underpinning thewide spectrumof behavior effects triggered by corticosteroids/stress growths, researchers should be able tobetter define new targets for therapeutic intervention in stress-related disorders.

© 2007 Elsevier B.V. All rights reserved.

Keywords:StressHippocampusPrefrontal cortexBehaviorStructureSynaptic plasticity

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5622. Corticosteroid receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5623. Neuroplastic events triggered by corticosteroid receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

3.1. Electrophysiological actions—within and from the hippocampus . . . . . . . . . . . . . . . . . . . . . . . . 5623.2. Behavioral effects—multimodal assessment of cognitive performance . . . . . . . . . . . . . . . . . . . . . 5633.3. Structural effects—the hippocampus and beyond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564

4. “Endophenotypes” and targets of intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5665. Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

Saúde, CP II Piso 3, Universidade doMinho-Campus de Gualtar, 4710-057 Braga, Portugal. Fax:

o.pt (N. Sousa).

er B.V. All rights reserved.

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1. Introduction

The limbic system, and in particular the hippocampus and themedial prefrontal cortex (mPFC), serves pivotal roles in cog-nition (Squire and Zola, 1996) as well as in the regulation of thehypothalamic–pituitary–adrenal (HPA) axis. Accumulatingevidence shows that corticosteroid modulation of hippocam-pal and mPFC activity and plasticity may underlie someaspects of the physiological and behavioral effects of chronicstress. A brief overview of the functional characteristics ofcorticosteroid receptors will be presented, and their role as keyplayers of the stress-induced functional and structural effectswill be revisited, with the intention to provide an integrativeperspective on the underpinningmechanisms and their impli-cations in clinical settings.

2. Corticosteroid receptors

Based on differing biochemical and functional characteristics,two types of corticosteroid receptors were described in the ratbrain (Reul and de Kloet, 1985). The so-called Type I, or thehigh-affinity mineralocorticoid receptor (MR), is most denselylocalized in hippocampal and septal neurons, but is alsopresent in cortical neurons. The Type II or glucocorticoidreceptor (GR) is ubiquitously distributed in neurons and glialcells. Due to their pharmacological properties, MRs are acti-vated at low corticosterone (CORT) concentrations; in contrast,during the circadian peak or under stress conditions, MRsbecome saturated, with the actions of GR becoming moremanifest (Reul and de Kloet, 1985). These dual actions con-tribute to both modulation of basal neuronal function andregulation of the HPA axis activity.

Classically corticosteroid receptors are described as part ofa cytoplasmic multiprotein complex, which consists of onereceptor molecule and several heat shock proteins (hsp)including two molecules of hsp90, one hsp70, one hsp 56,and an immunophilin (for a review, see Smith and Toft, 1993;Hutchison et al., 1994). After ligand–receptor binding and dis-sociation of the hsp and immunophilin, a chain of phosphor-ylation steps result in increased affinity of the ligand-activated receptor for DNA binding domains (Bodwell et al.,1991). Ligand-activated GR and MR can regulate gene tran-scription by: (i) activation or repression of gene expressionthrough binding of steroid receptors to single, multiple, orcomposite glucocorticoid-responsive elements (GREs) that arepresent in the promoter region of glucocorticoid-responsivegenes (Zilliacus et al., 1995); (ii) repression of gene transcrip-tion activated by other transcription factors such as AP-1 andNFκB (Hayashi et al., 2004); (iii) in addition, GR and MR may“cross-talk” with other nuclear receptors and transcriptionfactors through as yet undefined mechanisms (e.g. seePatchev and Almeida, 1996). Since GR and MR share manysimilarities (structural homology, common agonists, hormoneresponse elements, and may be co-localized—van Steensel etal., 1996), uncoupling in their actions may lead to disruptedbehavior and physiology.

There are different variants of corticosteroid receptors.Alternative splicing of the 3′-end of the human GR (hGR) pre-

mRNA creates an hGRβ variant in addition to the commonhGRα (Yudt and Cidlowski, 2001; Geng et al., 2005); however,the latter does not hold true for the rat (Otto et al., 1997). Inaddition, expression of the human MR gene may result in theformation of at least three transcripts, which are derived fromtwo different promoters (Vazquez et al., 1998). In humans, thetwo main transcripts, MRα and MRβ, are translated into thesame amino acid sequence as they differ only in the 5′-untranslated exon-1; as the resulting protein is the same, thebiological significance of two variants is unclear, even thoughthere is the possibility of different translation efficiencies and/or stabilities of the transcripts (Zennaro et al., 1995). Interest-ingly, the MRα, but not the β, promoter was found to contain aGRE-like element (Kwak et al., 1993), and thus only the lattervariant is up-regulated after adrenalectomy, an effect that isreversed by the administration of corticosteroids. Importantly,all MR variants are expressed in the rat brain: for example, inthe hippocampus, MRα mRNA is highly expressed in CA2 andthe dentate gyrus, whereas MRβ and MRγ mRNA are evenlydistributed in the hippocampal pyramidal layer (Kwak et al.,1993).

The existence of alternative, non-classical, signaling path-ways of corticosteroid receptors also deserves some elabora-tion. Such a mechanism has long been thought to apply toother steroids, triggered by the observation of rapid changes incellular activity (in a time-period of seconds to a fewminutes);rapid effects of corticosteroids are also known (Mikics et al.,2004). As an example, we recently observed that corticoste-rone, but not aldosterone, activates mitogen-activated proteinkinases (MAPKs) in hippocampus-derived neurons; theserapid effects of CORT on ERK1/2 eventually converge on thegenome insofar that they up-regulate the expression ofphospho-p90/RSK, phospho-Erk1, and phospho-c-fos, thusdefining a novel CORT-induced signaling pathway in hippo-campal neurons (unpublished data).

3. Neuroplastic events triggered bycorticosteroid receptors

3.1. Electrophysiological actions—within and from thehippocampus

Themodulation of neuronal function by corticosteroids is welldocumented. One example is the induction of long-termpotentiation (LTP) in the hippocampus which shows a specificpattern: LTP is observed when corticosteroids are kept withinnormal basal levels (Diamond et al., 1992), but it is impairedwhen corticosteroid levels are elevated (e.g. during stress)when, presumably, both GRs and MRs are occupied. Impor-tantly, hypercorticalism is also known to facilitate long-termdepression (LTD) in the hippocampus (Diamond et al., 1992;Pavlides and McEwen, 1999; Krugers et al., 2005). Although theunderlying mechanism through which high corticosteroids/stress exert their electrophysiological effects is still largelyunknown, there is evidence for an involvement of glutamatergictransmission in this phenomenon (Kim et al., 1996). Indeed,increased glutamate and calcium influx, both of which impairsynaptic plasticity, have been described in conditions of hyper-corticalism. Interestingly, it has been suggested that the MRs

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and GRs function in a dual manner at the electrophysiologicallevel: while MR activity is thought to be important for main-taining the excitability and stability of networks, GR activationseems to suppress or normalize network activity (de Kloet et al.,2005). Earlier studies reported differential effects ofMRsandGRson hippocampal LTP (Pavlides and McEwen, 1999) and, morerecently, it was shown that MRs and GRs assume opposite rolesin the regulation of synaptic plasticity after exposure to stress-ors (Avital et al., 2006).

While all the above described effects were previously onlyknown for the hippocampus, recent studies describe theinfluence of corticosteroid status in the regulation of electro-physiological responses in other CNS regions, including themPFC (Rocher et al., 2004; Cerqueira et al., 2007). This finding isnot surprising when one considers that the hippocampusinnervates the PFC — hippocampal afferents, originating inthe pyramidal cells of the subiculum and ventral CA1 regions,travel through the fimbria–fornix system, and terminate in thePFC, where they establish glutamatergic contacts with bothpyramidal cells and interneurons (Jay and Witter, 1991;Laroche et al., 2000). Accordingly, the occurrence and strengthof LTP in the hippocampus–PFC pathway may serve as anindex of synaptic plasticity (Jay andWitter, 1991; Tierney et al.,2004). Our recent data showed that chronic stress in ratsimpairs LTP and subsequently synaptic plasticity within thehippocampal–PFC pathway (Cerqueira et al., 2007). Although itmay be argued that deficits in the hippocampus–PFC projec-tions result from damage in the projecting areas, these are, infact, unlikely explanations for the impairment of LTP in thePFC after hippocampal stimulation. First, although chronicstress can impose structural damage to particular subfields ofthe hippocampal formation (McEwen, 2001; Sousa andAlmeida, 2002) it does not affect the volume and number ofneurons in the subiculum and CA1 (Sousa et al, 1998;Cerqueira et al., 2007). Second, our observation that identicalstimulation intensities produced similar baseline postsynap-tic potentials (waveform and amplitude) in stressed andcontrol animals indicates that the connecting pathway isintact. Finally, LTP induction in the hippocampus–PFC path-way has been shown to be impaired after a single episode ofacute stress (Rocher et al., 2004), a condition which impairsworking memory while facilitating hippocampus-dependentmemory storage (Shors, 2004). Interestingly, as in the hippo-campus, stress-induced impairment of synaptic plasticity inthe PFC appears to be NMDA-dependent since co-treatmentwith ifenprodil (an NMDA2Rb antagonist) ameliorates, at leastpartially, the impairment (Cerqueira, 2006).

3.2. Behavioral effects—multimodal assessment ofcognitive performance

Coordinate actions mediated by MRs and GRs in higher brainareas (e.g. neocortical regions and limbic areas such as hip-pocampus, nucleus accumbens, septum, bed nucleus of striaterminalis and amygdala) are the route through whichcorticosteroids influence emotional and cognitive behaviors.Again, corticosteroids exert dual effects in behavior: remark-ably, while sustained elevations of these hormones triggerbehavioral deficits, the acute release of stress hormones has apositive impact on certain behaviors. Importantly, in condi-

tions of eustress, corticosteroids influence information pro-cessing and cognitive function so as to facilitate behavioral(coping) adaptation to stress and restoration of basal HPA axisresponses by activating MR and GR in the hippocampus andPFC.

In fact, stress hormones, including corticosterone, releasedduring learning (every novel condition triggers a stressresponse), are necessary for establishment of enduringmemories. Several studies, using different behavioral para-digms, have revealed that the acute release of corticosteronethat occurs in association with training (similar levels to thosefound after exposure to stress) strengthens spatial memory ina time- and context-dependent manner (Sandi and Rose, 1994;Lupien and McEwen, 1997; Sandi et al., 1997). Furthermore,corticosterone administered after training facilitates extinc-tion of passive and active avoidance responses, therebypromoting the elimination of behaviors that are no longerrelevant (Bohus et al., 1982). Importantly, all of these effectsseem to depend on GR activation, as revealed by the use ofreceptor specific antagonists (Oitzl and de Kloet, 1992; Korteet al., 1996; Roozendaal et al., 1996) and in mice with targeteddeletions of the GR (Oitzl et al., 1997). However, sinceadrenalectomy (ADX) impairs the consolidation of spatialmemory (Oitzl and de Kloet, 1992), exploratory behavior(Veldhuis and de Kloet, 1983), and behavioral reactivity (Oitzlet al., 1993), it may be assumed that the MR/GR interplay iscrucial for hippocampus-dependent behavior. On the otherhand, sustained activation of GR results in deficits in spatialreference memory (McEwen and Sapolsky, 1995), even if onlytransiently (Sousa et al., 2000).

The spectrum of corticosteroid-induced cognitive deficitswas more recently recognized to extend beyond hippocam-pus-dependent tasks, to others, such as spatial workingmemory and behavioral flexibility (Cerqueira et al., 2005b).Spatial working memory, defined as the ability to transientlyhold and manipulate information “on line” and use it to guidebehavior (Goldman-Rakic, 1995), is considered to be a distinctfunction of the hippocampal–PFC interaction, while behavior-al flexibility (the ability to deal with a new set of rules) isregarded to be a typical PFC-dependent task (de Bruin et al.,1994). We recently showed that both chronic stress andmanipulations of the corticosteroid milieu (including stressexposure, ADX, and CORT and DEX treatments) have anegative impact on these behaviors; however, the impair-ments were more striking in stressed and DEX-treatedanimals than in CORT-treated animals (Cerqueira et al.,2005b, 2007). Interestingly, the removal of corticosteroids byADX also proved to be deleterious for PFC function since itimpaired behavioral flexibility, albeit without affecting spatialworking memory (Cerqueira et al., 2005b). This apparentbehavioral mismatch in conditions of MR unoccupancymight reflect the relative insensitivity ofmany currentworkingmemory tests for revealing subtle impairments in PFCfunction. In fact, in a delayed-non-matching-to-place task,another working memory paradigm (Mizoguchi et al., 2004),ADX only induced deficits when the task was made increas-ingly difficult, confirming that MR unoccupancy triggersmilder behavioral deficits in PFC-dependent tasks.

The finding that chronic CORT administration also inducesmilder deficits than those caused by chronic stress led us to

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hypothesize that othermediators, besides those resulting fromMR unoccupancy alone, might contribute to stress-inducedimpairments. One of these mediators is likely to be corticotro-pin-releasing hormone (CRH) which is released in severalregions of the CNS as part of the stress response (de Kloet,2004). Our recent studies confirmed that chronic infusion ofCRH into the ventricular system induces working memorydeficits (Cerqueira et al., in press). Thus, it seems that CRH, apeptide with high affinity for CRH receptor 1 (CRH.R1), mightalso contribute to the effects of chronic stress on PFC function.The abovementioned effects of CRH onworkingmemory couldnot be reproduced by treatment with urocortin, a mixedagonist of the CRH.R1 and CRH.R2. Therefore, even allowingfor the relative insensitivity of the Morris spatial workingmemory paradigm, these data suggest that, similarly to whatwas reported above for GRs and MRs, concurrent activation ofCRH.R2 can counteract adverse CRH.R1-mediated effects.Furthermore, as discussed below, this interpretation is sup-ported by structural observations since only CRH-treatedanimals display volumetric reductions in the PFC. In summa-ry, these findings suggest complementarity between theactions mediated by CRH.R1 and CRH.R2: while CRH.R1mediates the effects of stress, CRH.R2 predominantly con-tributes to the recovery of homeostasis (de Kloet, 2004). Aninsightful approach to this issue is the use of CRH.R2 selectiveagonists in combination with CRH or chronic stress. Ourpreliminary work shows that chronic i.c.v. administration ofthe CRH.R2-specific ligands urocortin2 or urocortin3 fails toimpair working memory, but rather confers beneficial effects(unpublished).

3.3. Structural effects—the hippocampus and beyond

Numerous data show that chronic stress results in reduced MRand GR expression and binding sites in the brain, and muchattention has focused on such changes in the hippocampusgiven its essential inhibitory role in the regulation of the HPAaxis (Feldman et al., 1995). One of themajor concerns addressedin the “glucocorticoid-cascadehypothesis” (Sapolsky et al., 1986)was themechanism throughwhich stress induces downregula-tion of corticosteroid receptors. Three main hypothesis wereconsidered: (i) that levels of glucocorticoids beyond a certainthreshold rendered corticosteroid receptor-bearing hippocam-pal neuronsmore vulnerable to excitotoxic aminoacids (such asglutamate); (ii) a direct neurodegenerative effects of corticoster-oids on hippocampal neurons, leading to reduced cell numbers;and (iii) a neuritic neurodegenerative process.

While the first possibility proved to be accurate, with sub-sequent proofs of glucocorticoid potentiation of the neurotox-ic effects of a variety of insults such as glutamate (Sapolskyand Pulsinelli, 1985; Lu et al., 2003), the alternative hypothesisof direct corticosteroid-mediated neurodegenerative processhas been controversial; for examples, questions have beenraised regarding the subpopulation of targeted neurons andthe magnitude of effects. Indeed, after initial reports claimingthat hypercorticalism induces hippocampal pyramidal cellloss (Sapolsky et al., 1985), later studies indicated that neitherchronic stress exposure nor corticosterone administrationleads to significant hippocampal neuronal loss (Sousa et al.,1999, 1998). On the other hand, administration of a GR agonist,

in a context of MR unoccupancy, was found to induce apopto-sis in the dentate granule and CA3 pyramidal cell layers (Sousaet al., 1999; Almeida et al., 2000). Interestingly, co-administra-tion of an MR agonist was seen to attenuate GR-mediatedneuronal death (Sousa et al., 1999). Moreover, ADX was foundto lead to a dramatic apoptosis of dentate granule cells(Sloviter et al., 1993; Sousa et al., 1997). Additional evidenceof the importance of MR and GR to the structure of thehippocampal formation derives from studies using transgenicmice; while genetic disruption of MR leads to dentate granulecell degeneration, GR−/− mice do not display signs of hippo-campal degeneration (Gass et al., 2000).

Since the number of dentate hippocampal cells is alsodependent on postnatal neurogenesis, observations thatstress/hypercorticalism negatively regulate hippocampal neu-rogenesis (Gould et al., 1991) stimulated much researchactivity in the field. Our own contributions to this area includethe demonstration that glucocorticoid treatment inducesarrest of the neural cell cycle (Crochemore et al., 2002) andapoptosis in neuronal progenitors and mature neurons(Crochemore et al., 2005); the molecular machinery involvedin these processes includes p53 and p21 as well as pro- andanti-apoptotic members of the BCl2 family of proteins(Almeida et al., 2000; Crochemore et al., 2002).

In an attempt to better discriminate the role of MR/GR inthe above processes, we performed experiments on primarypostnatal hippocampal cultures that included a large numberof mature neurons expressing both GR and MR (Crochemoreet al., 2005). The results of those studies showed that DEXtargets neurons (microtubule-associated protein 2-positivecells) for death through apoptosis and that this GR-mediatedcell death could be counteracted by the prototypic MR agonistaldosterone. Moreover, both spirolactone and another MRantagonist (RU28318) accentuated DEX-induced apoptosis.Together, these findings indicated that GRs can act directlyto induce hippocampal neuronal death and that demonstra-tion of their full apoptotic potency depends on the attenua-tion of the survival-promoting actions mediated by MR(Crochemore et al., 2005).

Corticosteroid-induced behavioral deficits may also beattributed to the atrophy of hippocampal cell neurites. Workfrom McEwens' laboratory demonstrated the induction of cellatrophy in CA3 apical dendrites in the rat (Watanabe et al.,1992; Magarinos et al., 1997); other laboratories extended thosepioneering observations to other hippocampal layers (Sousaet al., 2000) and species (Fuchs et al., 1995). Glucocorticoidshave also been implicated in the regulation of hippocampalsize in humans. For example, magnetic resonance imaging(MRI) has shown that glucocorticoid levels correlate negativelywith hippocampal size and cognitive function (Lupien et al.,1998). That study was preceded by other MRI studies: one fromSheline et al. (1996) described hippocampal atrophy indepressed patients, a condition generally characterized byelevated glucocorticoid secretion; the other by Starkman et al.(1992) reported decreased hippocampal volumes in hypercor-tisolismic patients suffering from Cushing's syndrome. Whilebolstering the view that ‘stress is bad for the brain’ (Sapolsky,1996), later studies demonstrating that correction of thehypercortisolemic condition can reverse hippocampal atrophyand improve cognition (Starkman et al., 2003) argue against

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a major causal role for cell death in cognitive impairment.Indeed, as previously discussed (Sousa andAlmeida, 2002), thehippocampus displays remarkable structural plasticity thatprimarily consists of loss and/or remodeling of dendrites andsynapses. Based on numerous observations showing that highglucocorticoid levels initiate dendritic atrophy and synapticloss among hippocampal neurons (Watanabe et al., 1992;Magarinos et al., 1997; Sousa et al., 2000), we proposed that GRactivation impairs hippocampal function by compromisingneuronal plasticity. Furthermore, data showing that an inter-vening stress-free period can reverse both hippocampalatrophy and the associated hippocampus-dependent behav-ioral deficits (Sousa et al., 2000), emphasize the transientnature of some of the deleterious effects of GR activation; thetransient effects are more explicable by dendritic atrophy andregrowth than by neuronal death.

Until fairly recently, studies of the electrophysiological,morphological, and behavioral actions of corticosteroids werelargely confined to the hippocampus even though severalstress-related disorders, including anxiety (Weniger et al.,2006) depression (Fossati et al., 2004), post-traumatic stressdisorder (Chen et al., 2006), and schizophrenia (Suzuki et al.,2005), have been associated with volumetric alterations in theamygdala and prefrontal areas. Our recent work has shownthat PFC-dependent behavioral deficits induced by chronicstress correlate with volume reductions in this brain region(Cerqueira et al., 2007). Moreover, these atrophic changes wereshown to be mediated through increased levels of CORT(Cerqueira et al., 2005b). Curiously, neither chronic stress norhypercorticalism influenced PFC neuronal numbers. On theother hand, exclusive GR activation by DEX triggered volu-metric atrophy and significant neuron losses in layer II of thePFC; as in the hippocampal formation, these deleterious GR-mediated actions could be counteracted by MR activation.

Intriguingly, the results of an in vivo MRI study revealedthat chronic DEX treatment results in volumetric reductionsthat are restricted to the left cingulate cortex (Cerqueira et al.,2005a). This new finding suggests greater vulnerability of theleft cingulate to the high corticosteroid levels and, probably,stress. Similar selective vulnerability of the left hemisphere toglucocorticoid effects was subsequently recognized in thehuman brain and, importantly, a recent MRI study reported anassociation between impaired regulation of the HPA axis andreduced size of the left cingulate cortex (MacLullich et al.,2006). The mechanisms underpinning this hemisphere-selec-tive susceptibility are unknown but deserve future investiga-tion. For instance, recent work revealed higher basal levels ofapoptosis in the left hippocampal dentate gyrus than thecontralateral hippocampal formation (Silva et al., 2006). Giventhat the hippocampal–PFC connections are largely ipsilateralobservations might be interrelated and of importance for ourimproved understanding of the neuroanatomical basis ofbrain pathology.

Remodeling of the neuropil by stress/hypercorticalismicstates is suggested by the fact that these states are associatedwith volumetric atrophy of the mPFC that is not accompaniedby a reduction in PFC neuron numbers. Indeed, corticosteroidstatus (high-dose corticosterone or DEX) was shown to pro-duce significant decreases in the total length and number ofspines in the apical dendrites of layer II/III pyramidal neurons

without any influence over the structure of basal dendrites(Cerqueira et al., in press). Importantly, the remodelingconsisted of increased dendritic branching in the medialportions of the apical dendrite and concomitant reductionsin dendritic arborization at the distal end portions; however,the number of dendritic branches was not subject to cortico-steroid influences. Except for the observed reduction in thetotal length of the apical dendrites, these findings wereconsistent with previous reports on the effect of chroniccorticosterone treatments (Wellman, 2001). Since both CORTand DEX had similar impacts, it may be concluded that thecorticosteroid-induced changes in the dendritic arborizationof mPFC pyramidal cells are mediated by GRs.

Interestingly, the morphology of the basal dendrites isneither affected by pharmacological manipulations of thecorticosteroid milieu (Cerqueira et al., in press) nor by stress(Radley et al., 2004; Cook and Wellman, 2004). The selectivevulnerability of the apical dendrites to manipulations of thecorticosteroid environmentmost likely reflects the topograph-ical distribution of inputs to layer II/III pyramidal cells of thePFC: whereas the soma and basal dendritic tree are innervatedby thalamic projections (Shibata, 1993), afferents from limbicstructures, including the hippocampus, terminate in moresuperficial layers (Swanson and Cowan, 1977), where theypreferentially contact apical dendrites. Furthermore, althoughboth the limbic and thalamic fiber systems are glutamatergic,their postsynaptic actions are primarily mediated by iono-tropic NMDA receptors (Rudolf et al., 1996) and metabotropic(AMPA) glutamate receptors (Pirot et al., 1994), respectively.Interestingly, layer II of the mPFC, where the apical dendritesof pyramidal neurons are located, is endowed with extra-synaptic NMDA.R2B-containing receptors which play a crucialrole in corticosteroid-induced excitotoxicity (Lu et al., 2003).Demonstrating a role for NMDA.R2B-containing receptors inthe mediation of corticosteroid-induced dendritic atrophy inthe mPFC, we recently showed that administration of theselective NMDA.R2B antagonist, ifenprodil, abrogates cortico-sterone- and DEX-induced dendritic atrophy (Cerqueira, 2006).Although not directly examined, it seems unlikely that AMPAreceptors, which transduce thalamic-to-prefrontal cortexsignals, play a major role in corticosteroid/stress-induced re-modeling of the apical dendritic tree since they are predom-inantly clustered in the basal dendrites and soma (Vickerset al., 1993). Nevertheless, activated AMPA receptors arethought to contribute to protection against glutamate-inducedneurotoxicity (Wu et al., 2004) by increasing the expression ofbrain-derived growth factor (Lauterborn et al., 2000).

Interesting results have also emerged from studies on theeffects of ADX (absence of MR/GR activation) on PFC structure.Whereas ADX does not affect volumes and neuronal numbers,this manipulation leads to atrophy of the apical dendrites(Cerqueira et al., in press). In contrast to that observed afterexposure to GR-activating ligands, however, the loss of“dendritic-material” after ADX is confined to peri-somalregions, with the distal tufts in layer I being unaffected.Different mechanisms might underlie the distinct topographyof apical tree impoverishment in ADX vs. corticosteroid-treated animals. The results of one recent study (Stanwood etal., 2005), which revealed that mice lacking dopamine D1receptors (primarily localized in theproximalportions of apical

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dendrites—Bergson et al., 1995) display structural reorganiza-tion of these apical dendrites, add support to the hypothesisthat the induction of a hypodopaminergic status may beresponsible for ADX-induced alterations in the architecture ofthe mPFC (Mizoguchi et al., 2000). Another possibility is thatADX triggers a deafferentiation process (Mizrahi and Libersat,2002).

The above-discussed influences of GR andMR activation onthe morphology and number of neurons in the hippocampusand mPFC correlate with the behavioral changes seen aftermanipulation of the corticosteroid milieu. Briefly, whiledendritic/synaptic reorganization andmild behavioral impair-ments occur after concomitant MR and GR activation,exclusive GR activation is followed by hippocampal and PFCneuronal losses and marked atrophy of apical dendrites aswell as profound deficits in reference and working memoryand behavioral flexibility. It is also important to note thatvariations in the corticosteroid milieu that trigger changes incorticosteroid receptors activation in other brain regions,particularly in the extended amygdala, are also likely to playa determinant influence on behavior and synaptic plasticity.Interestingly, there is evidence for intra-regional specificity inthe vulnerability to MR/GR activation within inter-dependentbrain circuits. This gives rise to the notion of a network ofbrain areas thatmediates the stress response, providing a newconceptual framework uponwhich neuroplastic interventionsto counteract the deleterious effects of stress on the brainmaybe based (Fig. 1).

Fig. 1 – Schematic representation of the global impact of stress upcortex. These effects are mediated by an imbalance of normal MR/function of these brain regions. Importantly, all these factors seemresults in a dysfunction of the HPA axis, that perpetuates the burd

4. “Endophenotypes” and targetsof intervention

Several issues remain unresolved in the field of stressresearch, one of the most fundamental questions being why,under seemingly similar conditions, some individuals aremore vulnerable to stress-induced brain pathology. The widespectrum of reactions to psychosocial challenges in thenormal population varies between two extremes: the abilityto mount a robust fight/flight response versus an apparentpassive conservation/withdrawal response (Bracha, 2004;McEwen, 2004).

Individual variations in regulation of the HPA axis (Petrideset al., 1997; Singh et al., 1999) might contribute to vulnerabilityand may thus serve as a good candidate for establishing an“endophenotype”. Variations in HPA axis regulation mayresult from the programming effects of corticosteroids duringcertain phases of life, but might be also linked to geneticdifferences. As an example, common polymorphisms in theGR gene are associated with different responses to stress(Wust et al., 2004) and some of them (e.g. BclI and ER22/23EK)are associated with altered susceptibility to develop majordepression (van Rossum et al., 2006). Indeed, it has beenshown that the response to antidepressants correlates withsome of these polymorphisms (van Rossum et al., 2006).Importantly, genetic manipulation of corticosteroid receptorsin mice confirms that an altered GR signaling is implicated in

on the structure of the hippocampal formation and prefrontalGR activation and trigger impairments in the connectivity andto be linked and potentiating each other, which ultimatelyen of stress and predisposes to disorders of the CNS.

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the pathogenesis of depression. More specifically, mice withGR reduction, similar to depressed patients, display increasedhelplessness after stress exposure, in parallel with a disin-hibited HPA axis (Ridder et al., 2005).

Environmental and experience-related factors, some orig-inating in early life, can also add to imbalances in the HPAaxis. There is now convincing evidence that supports earlysuggestions that early life experience triggers changes in thestress response and in emotionality that persist into adult-hood (Heim and Nemeroff, 1999). One example of theprogramming effects of corticosteroids is “handling,” a briefdaily separation of ratmother and pup.When tested as adults,handled animals show reduced emotionality and reducedadrenocortical reactivity (Levine and Mullins, 1966); this pro-cedure also results in increased GR expression in the brain,lower stress-induced corticosterone levels, and improved cog-nitive function in terms of spatial learning (Issa et al., 1990). Incontrast, a more severe procedure (‘maternal separation’ in-volving maternal–pup separations for 3–6 h per day) yieldsadult animals that express fewer GRs in the brain, in associ-ation with hypercorticalism and impaired spatial learning(Plotsky and Meaney, 1993). Exposure to high levels of gluco-corticoids during the neonatal period has also been shownto have damaging effects, manifest as reduced brain weight(Huang et al., 1999), impaired neuronal myelination (Dunlopet al., 1997), widespread reduction of dendritic spines (Anto-now-Schlorke et al., 2003), and a reduced number of neuralprecursor cells (Scheepens et al., 2003). All these changesmight conceivably underlie alterations in social behavior andlearning processes, and are believed to be caused by elevationsin glucocorticoid levels (Neal et al., 2004). Lastly, both animaland human studies suggest that an altered adrenocorticoste-roid milieu during vulnerable periods of neurodevelopmentcan impair an individual's resilience to stress in adulthood(McEwen, 2004). Interestingly, these subjects, and in particularthe females, display increased anxiety under basal conditionsand are more vulnerable to stress-related mental illness (inparticularly depression-like behavior) later in life (Oliveiraet al., 2006). Here it is worth noting that Oliveira et al. (2006)showed that GR activation is more deleterious than the co-activation of MR and GR.

AhyperactiveHPA axis is known to constitute an added riskfor many disorders associated with chronic stress, aging, andneurodegeneration, and/or with disturbances in cognition,mood, and affect. The experimental studies described aboveshow that changes in corticosteroid hormones, as a result ofstress or exogenous manipulations, impair the function of thebrain by acting directly upon neuronal function and cell/tissuestructure. Although not addressed in this review, it should alsobe mentioned that MR and GR regulate monoamines, such asserotonin, as well as the expression of peptides in the limbicsystem that have an important bearing on mental well-being(Joels and Van Riel, 2004; McEwen, 2004; de Kloet et al., 2005).Only by taking an integrated approach to understanding thedifferent modalities through which corticosteroids may con-tribute to an individual's susceptibility (or resilience) to stress-relateddisorders of thebrain, andby awareness of the intimatelinkbetween theareasof thebrain that regulatemood, anxiety,and cognition, can we expect to be on the right track towardsdeveloping effective treatment strategies.

5. Conclusions and future perspectives

In summary, the evidence reviewed here indicates that MRsand GRs assume opposite roles in regulating synaptic plastic-ity, especially under stressful conditions. Besides the hippo-campus, recent data demonstrate that MR and GR exertdifferential control over the structure of other brain regionssuch as the mPFC. MR activation, possibly by recruiting otherplayers (e.g. growth factors), seems to be prerequisite for‘positive’ neuroplastic events, whereas GR appears to bedetrimental for the neuroplasticity that is required for coping(physiologically and behaviorally) with the demands imposedby stress upon an individual. We propose that the finaloutcome of the stress response depends on the nature of thestressful stimulus (as well as previous experience) and on therelative activation of MRs, GRs, and other neuromodulatorysystems.

This review used the hippocampal–PFC connection toillustrate the need to approach the study of the impact ofcorticosteroids/stress on brain function from the perspectiveof networks, i.e. extending beyond the hippocampal–hypo-thalamic pathway that has dominated research in this fieldover the last 2 decades. Indeed, if the stress response is‘designed’ to facilitate successful adaptation, it follows thatthis would be best served by recruiting collateral integrativemechanisms to assess and interpret information impingingon multiple sensors, to apply facilitating or inhibiting modu-lation, and lastly, to execute appropriate neurobehavioral andphysiological responses. In this context, PFC-dependentbehavioral flexibility seems to be a critical component of theadaptive network, and its proper functioning clearly dependson intact neural inputs from the hippocampus. One futurechallenge will be to examine whether strategies to promotesynaptic reinforcement might serve to ameliorate the impactof stress on the brain. Another will be to systematicallyexplore which of the many stress-responsive brain regions(hippocampus, PFC, amygdaloid complex, septum, nucleusaccumbens, among others) succumb to the damaging effectsof stress, thus ‘short circuiting’ the neural circuitry. Thesedeliberations lead to the view that excessive stress/inade-quate bufferingmechanismsmay lead to a progressive ‘neuraldisconnection syndrome’.

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