Functional actions of corticosteroids in the hippocampus

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European Journal of Pharmacology 583 (2008) 312 – 321 www.elsevier.com/locate/ejphar

Review

Functional actions of corticosteroids in the hippocampus Marian Joëls ⁎ SILS-CNS, University of Amsterdam, Kruislaan 320, 1098 SM Amsterdam, The Netherlands Accepted 21 November 2007 Available online 19 January 2008

Abstract Corticosteroid hormones are released in high amounts after stress. The hormones enter the brain compartment and bind to high affinity mineralocorticoid receptors –particularly enriched in limbic regions– as well as to lower affinity glucocorticoid receptors which are more ubiquitous. Shortly after the stressful event, corticosteroids (in concert with specific monoamines and neuropeptides) have the potential to increase cellular excitability in subfields of the hippocampus, like the CA1 area. These effects are rapid in onset and occur via a nongenomic pathway. At the same time, however, the hormones also start slower, gene-mediated processes. These cause attenuation of excitatory information flow through the CA1 hippocampal area. Induction of long-term potentiation at that time is impaired. This may help to normalize hippocampal activity some hours after the stressful event and preserve information encoded within the context of the event. These adaptational effects of the hormones may become maladaptive if the stressful event is associated with other challenges of the network (like ischemic insults) or when stress occurs repetitively, in an uncontrollable and unpredictable manner. In that case, i) normalization of activity seems to be less efficient (particularly when other limbic areas like the amygdala nuclei are activated during stress), ii) induction of long-term potentiation is hampered at all times and iii) serotonin responses are attenuated. This may contribute to the precipitation of clinical symptoms in stress-related disorders such as major depression. A better understanding of the corticosteroid actions could lead to a more rational treatment strategy of stress-related disorders. © 2008 Elsevier B.V. All rights reserved. Keywords: Glucocorticoid receptor; Mineralocorticoid receptor; Electrophysiology; Corticosterone; Glutamate; Serotonin; Noradrenaline; Long-term potentiation; Chronic stress

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute stress . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. CA1 hippocampal area . . . . . . . . . . . . . . . . . . 2.2. CA3 area and dentate gyrus . . . . . . . . . . . . . . . 2.3. Importance of corticosteroid actions after acute stress . . 3. Chronic stress . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. CA1 hippocampal area . . . . . . . . . . . . . . . . . . 3.2. CA3 region . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Dentate gyrus. . . . . . . . . . . . . . . . . . . . . . . 3.4. Consequences of chronic overexposure to corticosteroids 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Tel.: +31 20 5257626; fax: +31 20 5257709. E-mail address: [email protected]. 0014-2999/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.11.064

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1. Introduction Potential disturbances of bodily functions, be it from internal or external sources, are processed in the brain and perceived as ‘stress’ by the individual. Signals from brainstem and limbic areas activated by the stressful conditions funnel through the hypothalamus from where they can activate two systems, i.e. the sympatho-adrenomedullar system and the hypothalamo-pituitary–adrenal system (De Kloet et al., 2005; McEwen, 2007; Morilak et al., 2005). As a result circulating levels of adrenaline and corticosterone (in rodents; cortisol in humans) respectively are elevated. Adrenaline can indirectly lead to enhanced release of noradrenaline from locus coeruleus neurons. Corticosterone itself can easily pass the blood–brain barrier and reach all brain cells. At those sites where receptors are enriched, the hormone exerts its actions. In the past, two receptor types have been recognized to which corticosterone can bind (De Kloet et al., 1998). Low levels of the hormone suffice to substantially occupy the mineralocorticoid receptor. This receptor is particularly enriched in all hippocampal subfields, the central amygdala, lateral septum and motor nuclei in the brainstem. When corticosteroid levels rise, e.g. after stress or at the circadian peak of release, the second type of receptor –i.e. the glucocorticoid receptor which has a tenfold lower affinity for the hormone– also becomes activated to a large extent. This receptor is widespread, though enriched e.g. in the hippocampal CA1 area, the dentate gyrus and the hypothalamic paraventricular nucleus. Principal neurons in the hippocampal CA1 area and dentate gyrus therefore shuttle between a condition of predominant activation of mineralocorticoid receptors (under rest, at the circadian trough) and a situation where both receptor types are substantially occupied such as occurs after stress. After binding of corticosterone to its receptor, chaperone proteins dissociate and the receptor–ligand complex moves to the nuclear compartment (Duma et al., 2006; Pascual-Le Tallec and Lombes, 2005). It can either bind in homodimer complexes to recognition sites in the DNA and thus activate gene transcription or interact as monomer with other transcription factors, which usually results in repression. In both cases, though, the protein content of the cell will change, which gradually but persistently alters particular cell functions. In addition to these slow gene-mediated pathways, corticosteroid hormones also exert rapid nongenomic effects which will be discussed in detail in the next chapter (Di et al., 2003; Karst et al., 2005). It is well-known that stress via corticosteroid hormones affects behavior (see for reviews Kim and Haller, 2007; Lupien et al., 2007; Shors, 2006). Most likely this is established through altered function of cells and networks that are critically involved in the behavioral processes. Although it was already appreciated in the early 1970s that corticosteroid hormones can change cell firing of hippocampal neurons within 30 min (Pfaff et al., 1971), advanced electrophysiological studies over the past two decades have resolved in much greater detail how physiological properties of cells in the hippocampus but also in other areas are affected by these stress hormones. In the next section we will review the effects of brief rises in corticosteroid level on

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cell and network function. Most data pertain to studies of the hippocampal formation; for findings in other parts of the brain we refer to a more extensive review (Joëls et al., 2007). The observations seen after a brief pulse application of corticosterone are exemplary for what might happen after a single stressful situation. However, often the organism experiences repetitive exposure to stressful conditions, usually in an uncontrollable and unpredictable manner. This also changes brain function, under basal conditions (i.e. when the hypothalamo-pituitary– adrenal axis is not strongly activated) but particularly when the organism experiences a novel stressor against a background of chronic stress. The findings from chronic stress studies will be reviewed in Section 3 of this chapter. We will end with a brief summary and guidelines for future studies. 2. Acute stress A brief period of stress results in the release of monoamines (most notably noradrenaline), peptides like corticotrophin releasing hormone (CRH) and vasopressin, and corticosteroids entering the brain (Bale and Vale, 2004; De Kloet et al., 2005; Morilak et al., 2005). Most of these stress hormones primarily exert their function as long as they are released in substantial amounts, so that some hours after the stressful event their main effects have subsided. Actions of monoamines and peptides are described elsewhere in this volume. Corticosterone too exerts such rapid nongenomic and short-lasting effects. For instance, in the hippocampus the hormone increases the release probability of glutamate-containing vesicles, via a presynaptic route involving extracellular signal-regulated kinase1/2 (Karst et al., 2005; Olijslagers et al., 2006). Moreover, a postsynaptic K-conductance IA is reduced. Both effects critically depend on the mineralocorticoid receptor. In line with these findings it was observed that corticosterone also rapidly facilitates long-term potentiation (LTP) in the CA1 area (Wiegert et al., 2006), i.e. synaptic strengthening in response to high frequency stimulation which is presently the best-available neurobiological substrate for learning and memory formation (Lynch, 2004). The facilitation by corticosterone is seen when increased levels of the hormone are present at the moment of high frequency stimulation. Effectively, CA1 excitability can be enhanced shortly after stress, via nongenomic effects of corticosterone. Most other stress hormones (including monoamines and several peptides) exert similar excitatory effects, although this also depends on the hormone concentration and thus probably on the nature and severity of the stressor (for review see Joëls et al., 2007). Interestingly, the stress hormones seem to interact with each other. This was for instance demonstrated in the dentate gyrus, where corticosterone rapidly facilitates the effects of β-adrenoceptor agonists on long-term potentiation (Pu et al., 2007). Corticosterone, however, also starts gene-mediated events at the time of stress which will become apparent only hours later. Many physiological studies have used a protocol in which a pulse of corticosteroids is applied to a reduced slice preparation, and functional consequences are studied several hours later, i.e. when rapid effects by stress hormones have subsided. Because of the delayed effects it is also possible to expose the intact

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animal to stress and then examine the functional effects some hours later when slices have been prepared. Nearly all data discussed below were obtained with these two approaches. 2.1. CA1 hippocampal area The slow, gene-mediated and long-lasting effects of corticosteroid hormones in the hippocampal CA1 region are usually not seen when cells are studied under resting conditions, i.e. when their membrane potential is close to its resting state. Only when the membrane potential is shifted away from the resting state e.g. through the effect of neurotransmitters, do genemediated corticosteroid effects become apparent. Depolarization activates many different voltage-dependent ion currents. Of these, the calcium currents are most sensitive to variation in corticosteroid level. Thus, low levels of corticosterone, which mainly activate mineralocorticoid receptors, are associated with small amplitudes of voltage-dependent calcium currents (Joëls et al., 2003; Karst et al., 1994, 2000; Kerr et al., 1992). Additional activation of glucocorticoid receptors, such as occurs e.g. after a moderate novelty stress, significantly increases the amplitude of calcium currents; voltage dependency and kinetic properties are unaffected. In particular L-type sustained calcium currents are affected via the glucocorticoid receptor (Chameau et al., 2007). This involves DNA binding of

receptor homodimers (Karst et al., 2000). It is still not fully resolved whether the hormone targets the gene for the poreforming subunit of L-type channels or an auxiliary subunit which could be involved in surface expression of the calcium channels (Chameau et al., 2007). Interestingly, in the absence of corticosteroids L-type calcium currents also display a large amplitude (Karst et al., 1994). Overall this results in a typical U-shaped dose-dependency, which is seen for many effects of corticosterone in the CA1 area (Joëls, 2006). Not only calcium entry, but also calcium extrusion seems to be affected by corticosteroids (Bhargava et al., 2002). Collectively this indicates that several hours after a brief period of stress, intracellular calcium concentrations rise more profoundly upon depolarization of the CA1 cells. Although corticosteroid effects have also been described for particular K or Na current characteristics, these currents seem to be less conspicuously affected than the calcium currents (for review Joëls, 1997). Under physiological conditions enhanced calcium entry can easily be dealt with (see Fig. 1). One of the functional consequences could be that the calcium-dependent K current (IK(Ca)) is modulated. Indeed, with predominant mineralocorticoid receptor activation IK(Ca) is small, so that spike frequency accommodation –which is governed by IK(Ca)– is limited (Joëls and de Kloet, 1990). By contrast, several hours after a brief pulse of corticosterone (which activates glucocorticoid receptors), spike

Fig. 1. Several hours after exposure to stress and/or activation of glucocorticoid receptors, calcium (Ca) influx into hippocampal CA1 pyramidal neurons is increased (left). There is also evidence that Ca extrusion is impaired. Potentially this leads to enhanced intracellular Ca concentrations when neurons are depolarized. This may have various functional consequences. First (top), the firing frequency accommodation which is caused by activation of IK(Ca) and the afterhyperpolarization which occurs when IK(Ca) is deactivated at the end of the depolarizing input will be increased, causing attenuation of excitatory information flow through the CA1 area. This effect (coupled to other effects, see main text) is predicted to normalize the excitability that was temporary enhanced shortly after stress. Second (middle), enhanced intracellular Ca concentrations are known to suppress NMDA-receptor function. This may be one mechanism by which the induction of LTP is impaired several hours after stress. By raising the threshold for LTP induction, the information that was encoded shortly after stress will be preserved. However, all this comes at a cost. Thus, enhanced intracellular Ca concentrations especially when present for a longer period of time also impose a risk for cellular viability (bottom). Consequently, glucocorticoid receptor activation in combination with strong and/or prolonged depolarization may lead to increased vulnerability, as shown in this example for epileptogenesis in the kindling model of rats.

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frequency accommodation is strong (Joëls and de Kloet, 1989; Kerr et al., 1989). Thus, some hours after stress exposure CA1 pyramidal neurons will less efficiently transmit excitatory information. Of course, the enhanced calcium load may impose a risk on the integrity of CA1 pyramidal neurons, particularly when neurons are strongly depolarized. This may occur e.g. during ischemic or epileptic insults. Accordingly, there is ample evidence that the outcome of such conditions is worsened by stress (Smith-Swintosky et al., 1996; Karst et al., 1999; Krugers et al., 2000). It is still not quite clear how corticosteroids affect amino acid transmission in the CA1 area. Reductions in glutamatergic as well as GABAergic mediated transmission have been described, but these effects develop rather quickly and might be related to metabolic dysfunction; perhaps they are not gene-mediated (reviewed in Joëls, 1997). Less ambiguity exists with regard to corticosteroid effects on LTP. Nearly all reports agree that in the CA1 area the NMDA-dependent type of LTP is effectively evoked with predominant activation of mineralocorticoid receptors —i.e. when animals are not stressed (see review Kim and Diamond, 2002; Joëls and Krugers, 2007). By contrast, formation of LTP is largely hampered when high frequency stimulation is applied several hours after glucocorticoid receptor activation/stress; this only happens with moderate but not with strong stimulation protocols (Alfarez et al., 2002). Monoaminergic transmission is also affected by the hormones in a slow gene-mediated fashion. Several hours after stress or glucocorticoid receptor activation, inhibitory responses via serotonin-1A receptors are facilitated, via a process that requires binding of receptor homodimers to the DNA (Karst et al., 2000). Conversely, excitatory responses mediated via β-adrenoceptors are suppressed in a slow manner depending on glucocorticoid receptor activation (Joëls and de Kloet, 1989). The emerging picture is that CA1 neurons could be excited shortly after stress, while hormone levels are high (Joëls et al., 2006; Diamond et al., 2007). At the same time, however, a gene-dependent pathway is started which some hours later ‘puts a brake’ on CA1 cell activity. Excitatory transmission that reaches the cells at that time will be less effectively transmitted, inhibitory responses will be facilitated, while patterned input associated with learning of new information is hampered. This period can be interpreted as a phase in which the temporary arousal after stress is normalized and CA1 cells are relatively refractory to encoding of new information. 2.2. CA3 area and dentate gyrus The CA3 area in many respects resembles the CA1 area in its response to corticosterone, although CA3 cells are far less investigated. For instance, high concentrations of corticosterone, which substantially occupy glucocorticoid receptors, increase calcium current amplitude and IK(Ca)-dependent phenomena just like in the CA1 region (Kole et al., 2001). Moreover, predominant mineralocorticoid receptor activation in the CA3 region is associated with efficient LTP (via NMDAreceptors), while glucocorticoid receptor agonists impair LTP (Pavlides and McEwen, 1999). CA3 neurons –as opposed

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to CA1 cells– display spontaneous action potential bursts. Conditions resulting in predominant mineralocorticoid receptor activation are linked to a high incidence of bursting cells, while high levels of corticosterone result in fewer bursting cells (Okuhara and Beck, 1998). All of this fits with the idea that CA3 neuron activity too is normalized after the initial arousal during the first phase of the stress response. The dentate gyrus seems to respond differently to stress and corticosterone. This is partly caused by the fact that dentate granule neurons are subject to an active cell cycle even in adulthood (Kempermann et al., 2004). New neurons are continuously formed from proliferating cells residing in the subgranular zone, while young as well as mature neurons die by apoptosis. As stress is inversely related to neurogenesis and apoptosis, the ensuing change in cell population could indirectly affect physiological function of the dentate network (for reviews Fuchs et al., 2006; Joëls et al., 2007; Mirescu and Gould, 2006). The presently available data indicate, however, that this influence seems of limited importance (see below). Rather, stress, corticosterone or the absence of hormones changes functional properties of already existing (and surviving) neurons, which indeed markedly alters the dentate network function. Dentate granule neurons are exquisitely sensitive to the absence of corticosteroids. In that case, proliferation and apoptosis increase largely (Mirescu and Gould, 2006; Sloviter et al., 1989). Absence of corticosterone also results in a loss of distal dendrites in granule neurons (Wossink et al., 2001). Concurrent with these changes, glutamatergic transmission –both via AMPA and NMDA-receptors– is impaired (Joëls et al., 2001). In agreement, overall field responses to stimulation of perforant path input are reduced by 30% in the absence of corticosterone (Stienstra et al., 1998); LTP is impaired (Krugers et al., 2007). These changes in synaptic responsiveness occur even prior to alterations in the cell cycle and can be rapidly restored by in vitro application of corticosterone. Calcium current amplitude is increased in all cells (Karst and Joëls, 2001). Finally, it was observed that some but not all of the granule neurons can change their gene expression profile in the absence of corticosterone such that this increases their chances on survival (Nair et al., 2004). Collectively, this set of data is thought to signify that in the absence of corticosterone vulnerable (e.g. old) cells succumb because they are exposed to more calcium and cannot trigger genes that will help them survive, while other cells (i.e. those than can trigger survival genes like Bcl-2) succeed in resisting the apoptotic route. Dentate granule cells also differ from CA1 (and CA3) neurons with respect to their sensitivity to high corticosteroid concentrations. Concentrations that activate glucocorticoid receptors in and change function of CA1 neurons do not profoundly affect cell function in the dentate (Joëls, 2006). For instance, field responses and AMPA-receptor mediated synaptic responses, evoked by perforant path stimulation in the dentate, as seen with high corticosterone concentrations are quite comparable to responses observed when the steroid level is quite low (Stienstra and Joëls, 2000; Karst and Joëls, 2003). A similar apparent lack of glucocorticoid sensitivity was found for calcium current amplitude (Van Gemert and Joëls, 2006) and

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gene expression profiles (Qin et al., 2004). Stress or glucocorticoids were reported to have variable effects on LTP in the dentate gyrus; the overall effect depends on the type of stressor and the timing of stress exposure relative to high frequency stimulation, as well as the influence of inputs from the amygdala (Akirav and Richter-Levin, 1999; Bramham et al., 1998; Kavushansky et al., 2006; Korz and Frey, 2003, 2005; Pavlides et al., 1993; Yamada et al., 2003). Overall, the mineralocorticoid receptor seems to play a crucial role in the dentate gyrus. Activation of this receptor is important for controlling the cell cycle. Moreover, this receptor (rather than the glucocorticoid receptor) appears to determine the cellular function over a wide range of corticosterone concentrations. 2.3. Importance of corticosteroid actions after acute stress Electrophysiological studies over the past decades have clearly shown that hippocampal cell properties are profoundly altered over the course of several hours after stress, a process in which corticosteroid hormones play a prominent role. Shortly after stress exposure (while hormone levels are still elevated) CA1 cell activity can be raised, through the joint and probably interactive effects of noradrenaline, neuropeptides and (neuro) steroids (see Fig. 2). This phase may be involved in the initial stages of encoding. Activity in the CA1 area will be normalized some hours later, when gene-mediated corticosteroid effects have developed. Pyramidal neurons are at that time relatively refractory to renewed strengthening of synaptic contacts; only very salient information can surpass the threshold at that time. This may help to preserve the originally encoded information. The observations in the dentate gyrus already indicate that the slow gene-mediated normalization by glucocorticoids is not generalized in brain. Thus, delayed glucocorticoid effects are far less prominent in the dentate gyrus. Recent observations suggest that in the basolateral amygdala cells are even slowly excited instead of inhibited by glucocorticoids (Duvarci and Pare, 2007). Stress during behavioral situations which strongly involve amygdala (and dentate) networks might therefore have more lasting consequences than during situations that more heavily depend on CA1 activity. In our overview we strongly emphasized glucocorticoid effects that take place over the course of several hours after a single stressor, in male rodents. However, some studies have indicated that a single stressor can have even more delayed (N24 h) consequences, e.g. on CA1 spine morphology (Shors et al., 2001). Moreover, these effects were gender-dependent. Clearly, an overall understanding of the effect of corticosteroids and stress on limbic brain function will only be possible when more information is available from studies examining a wide time-frame, in the hippocampus as well as other areas (Diamond et al., 2007), in female and male organisms. 3. Chronic stress In addition to acute stress, individuals can also experience multiple episodes of stress, often in an unpredictable or uncontrollable manner. There is ample evidence that this leads to slow

Fig. 2. Schematic representation of excitability in the hippocampus during various phases of stress exposure. Under rest, the excitability in limbic regions is relatively low. LTP is efficiently induced, while factors that could predispose to vulnerability such as Ca load are restricted. Under these conditions, genemediated mineralocorticoid receptor-activated pathways play a major role and – particularly in the dentate gyrus– are in fact necessary to preserve neuronal integrity. Shortly after stress exposure, hippocampal excitability is thought to be raised and high frequency input leads to strong potentiation. This phase involves rapid nongenomic signaling pathways activated by (nor)adrenaline, peptides and corticosterone. These effects most likely persist as long as hormone levels are high (see top). When the rapid effects subside, delayed gene-mediated effects become apparent which were initiated at the time of stress exposure. These effects, which are mediated via nuclear glucocorticoid receptors (against a background of already activated mineralocorticoid receptors), fully develop by the time that hormonal levels are back to normal and most likely will last for several hours. Functionally, they normalize the activity that was raised during the initial stage of the stress response and preserve information that was acquired at that time. In this way, the organism is optimally prepared for a similar stressor in future.

changes in the limbic network (for more extensive review see Joëls et al., 2007). Most data were obtained in animal models of chronic stress. These range from repetitive exposure to several hours of restraint stress per day, to unpredictable (mild) stressors in a pseudorandom fashion or models of social stress. Some of the findings are reviewed below. 3.1. CA1 hippocampal area Chronic stress was found to only mildly affect the morphology of CA1 pyramidal neurons (Sousa et al., 2000; Woolley et al., 1990). However, it does induce a tissue plasminogen activator dependent decrease in the number of spines (Pawlak et al., 2005). When corrected for a small decrease in volume, the number of asymmetric synapses in the CA1 stratum lacunosum-moleculare was unaffected, while the postsynaptic density surface area was increased (Donohue et al., 2006). Recent observations indicate that effects of chronic stress on CA1 morphology may become more apparent when the HPA-axis is activated at the moment of investigation (Alfarez et al., 2008). Basal (passive and active) membrane properties of CA1 pyramidal cells are not consistently changed after chronic stress.

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Yet, remarkable changes were observed in calcium current characteristics, in a model for chronic (i.e. 21 days of) unpredictable stress (Karst and Joëls, 2007). While calcium currents under conditions of predominant mineralocorticoid receptor activation are small in naïve or handled animals, they are large in chronically stressed rats. This effect could be fully prevented by treating rats with a glucocorticoid receptor antagonist during the last 4 days only of the stress protocol. Interestingly, the responsiveness to corticosteroids was also affected by chronic stress (see Fig. 3). Compared to naïve rats –which show an increased calcium current several hours after glucocorticoid receptor activation– rats with a history of chronic stress showed a decreased current, while handled animals did not respond at all. The latter observation underlines that inclusion of both a handled and a naïve control group is very informative. Hyperpolarizing responses via the serotonin-1A receptor have also been investigated in the model of unpredictable stress. Responses, which in naïve or handled animals are small with predominant mineralocorticoid receptor activation, were found to be even smaller in animals with a history of chronic stress or corticosterone administration (Karten et al., 1999; Van Riel et al., 2003). Additional glucocorticoid receptor activation in tissue of chronically stressed rats did increase the response to serotonin, but not to the extent seen in naïve rats. As described in Section 2, LTP is efficiently evoked when corticosteroid levels are low. However, this is not true in animals with a history of chronic (unpredictable) stress. In these rats, it is very hard to induce LTP (Alfarez et al., 2003), like in naïve (or handled) rats

Fig. 3. Chronic unpredictable stress increases Ca-current amplitude (measured at 0 mV) in CA1 pyramidal hippocampal neurons, compared to the currents in handled control animals (grey bars). Treatment with the glucocorticoid receptor antagonist RU 38486 during the last 4 days of the 21-days stress protocol fully reverses these effects on the calcium current. Interestingly, handling as well as chronic stress altered the response to in vitro activation of glucocorticoid receptors (stippled bars), in this case by briefly applying 100 nM corticosterone to hippocampal slices. While glucocorticoid receptor activation in tissue from naïve control rats (bars left) causes an increase in Ca-current amplitude, no effect was seen in the handled controls or chronically stressed rats treated with RU 38486. In tissue from chronically stressed rats, corticosterone even reduced Cacurrent amplitude. These data support that glucocorticoid receptor mediated responses strongly depend on the history of the animal and underline that handled as well as naïve controls should be incorporated in the experimental design. Reproduced with permission from Joëls et al. (2007).

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exposed to high levels of corticosterone (Alfarez et al., 2002). Brief treatment with a glucocorticoid receptor antagonist towards the end of the stress protocol fully prevented the impairment in LTP (Krugers et al., 2006). Altogether, CA1 cell function as examined under basal corticosteroid conditions is markedly altered after chronic stress: Depolarization will lead to stronger calcium influx and the formation of LTP is largely hampered. In addition, CA1 cells may respond differently to glucocorticoid receptor activation. 3.2. CA3 region Many studies have described that chronic stress gradually leads to dendritic retraction in the CA3 area. This was observed with various stress protocols –such as prolonged corticosterone administration, chronic restraint as well as models of social stress– and also in various species (e.g. Magarinos and McEwen, 1995a; Magarinos et al., 1996). The effects in all cases pertained to the apical tree but not the basal tree. The retraction of dendritic branches was particularly strong in the middle third of the apical tree, i.e. the projection area of commissural/associational fibers (Kole et al., 2002). Furthermore, chronic stress also results in loss of simple asymmetric mossy fiber synapses, retraction of thorny excrescences and fewer postsynaptic densities (Sousa et al., 2000; Stewart et al., 2005). Presynaptically, more densely packed vesicle clusters were observed close to the active zone (Magarinos et al., 1997). The morphological changes could be prevented by treatment with a corticosteroid synthesis inhibitor, supporting an important role for glucocorticoid receptors (Magarinos and McEwen, 1995b). Moreover, treatment with NMDA-receptor antagonists, phenytoin as well as antidepressants protected against the effects of chronic stress (Kole et al., 2002; Watanabe et al., 1992). Physiologically, CA3 cells are also changed after chronic stress. It cannot be excluded that some of these changes occur secondarily to the morphological effects. For instance, in vivo a significant shift in current sources and sinks upon stimulation of afferents occurred in the apical dendrites and pyramidal cell layers of the CA3 field, consistent with atrophy of the apical dendrites (Pavlides et al., 2002). LTP evoked by stimulation of commissural and associational pathways –but not of mossy fibers– was suppressed after chronic stress, which again is consistent with the pattern of dendrite retraction. Suppression of LTP was also seen in slices after 3 weeks of social defeat and even 3 weeks after two defeat experiences in rapid succession (Kole et al., 2004). Chronic stress was furthermore found to increase the amplitude and decay-time of NMDA-receptor mediated responses in hippocampal slices, while non-NMDA responses were unaffected (Kole et al., 2002). This effect was blocked by the treatment with the antidepressant tianeptine during the chronic stress period. 3.3. Dentate gyrus Chronic stress suppresses neurogenesis in the dentate gyrus. This was observed in at least four different animal species (mice, rats, tree shrews and marmoset monkeys) and appears to

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generalize also across different paradigms (for overview see Fuchs et al., 2006; Joëls et al., 2007; Mirescu and Gould, 2006). Psychosocial or physical stressors all inhibited one or more aspects of the neurogenesis process, i.e. proliferation, survival, migration or differentiation. The effects of chronic stress on neurogenesis have been effectively blocked by antidepressants and glucocorticoid receptor antagonists. It should be realized that even after several weeks of stress, the suppression of granule cell number will only be limited (b 5%) relative to the total number of cells. But it cannot be excluded that such a temporary attenuation in cell birth –provided the affected cells are placed at a crucial position in the network– alters dentate function. However, if one studies dentate neurons shortly after several weeks of stress exposure, the effects of neurogenesis will not greatly alter dentate cell properties, as it takes several months for newborn cells to fully mature and become incorporated into the network. Granule cells examined shortly after a period of stress apparently do not differ from granule cells in naïve or handled controls. For instance, there are no differences in AMPA-receptor mediated responses to perforant path stimulation, no changes in calcium current and very few effects on single cell gene expression patterns (Karst and Joëls, 2003; Qin et al., 2004; Van Gemert and Joëls, 2006). The most prominent change is a reduced ability to induce LTP (Alfarez et al., 2003). Much more pronounced effects of a history of chronic stress were seen when dentate granule cells were acutely exposed to a high concentration of corticosterone. While granule cells in naïve rats are quite resistant to activation of glucocorticoid receptors, cells from animals with a history of chronic stress displayed a strong response to activation of this receptor. AMPA-receptor mediated responses were increased in amplitude (Karst and Joëls, 2003), the calcium current amplitude was found to be enhanced (Van Gemert and Joëls, 2006) and mRNA expression levels of AMPA-receptor or calcium channel subunits were significantly enhanced (Qin et al., 2004). In summary, when animals are under rest the influence of a recent history of prolonged stress is not very apparent from the functional properties of dentate granule cells. However, when these cells are exposed to high corticosteroid levels (e.g. after an acute stress situation) against a background of chronic stress, they respond much stronger than without such background. 3.4. Consequences of chronic overexposure to corticosteroids for hippocampal function Chronic overexposure to corticosteroids, such as occurs after prolonged episodes of stress, alters the function of hippocampal cells. In the CA1 area, calcium influx is regulated in an opposite way to what is seen in naïve animals, i.e. calcium currents are large with predominant mineralocorticoid receptor activation and reduced when glucocorticoid receptors become activated. This could have important consequences for the flow of information through this area and the vulnerability of CA1 neurons to adverse situations. It is predicted that after chronic stress, transfer of information is less efficient under conditions of predominant mineralocorticoid receptor activation, i.e. un-

der rest. Induction of LTP is also hard. When the animal experiences acute stress (against a background of chronic stress), less normalization of aroused activity will take place several hours after the stress exposure. All of this may lead to cognitive impairment. In addition, serotonin responses display overall attenuation which may add to the susceptibility to mood disturbances. In the dentate gyrus little effect of chronic stress will be observed when the animal is under rest. Yet, granule cells seem to become hyper-responsive to renewed stress exposure. Interestingly, similar observations were made in the amygdala. For instance, firing frequency of central amygdala neurons in vivo is reduced after footshock in control animals, but enhanced in animals previously exposed to prolonged cold stress (Correll et al., 2005). Habituation to footshock was attenuated after cold stress. In the BLA, the number of spontaneously firing cells was increased after cold stress, as was the response to footshock. These functional data may be related to morphological observations suggesting more prominent BLA activity after chronic stress. Thus, 10 to 21 days of restraint, which reduces dendritic complexity in the hippocampal CA3 region, increases the total dendritic length and spinogenesis of pyramidal/stellate but not bipolar cells in the basolateral amygdala (Vyas et al., 2002). This depends on the type of stress, as 10 days of unpredictable stress did not change the morphology of pyramidal/stellate BLA cells and reduced dendritic length of the bipolar cells. In general, limbic neurons seem to become more excitable, be it under conditions of rest or with an activated hypothalamopituitary–adrenal system. The available data emphasize that it is important to specifically address the latter condition, as otherwise many effects of chronic stress on cell properties could remain unnoticed. This may be a region-specific phenomenon, of which the consequences depend on the behavioral situation that is studied. 4. Discussion Since the observation more than thirty years ago that adrenal corticosteroids influence hippocampal firing, many studies have appeared that help understand exactly how these hormones affect different neuronal populations during various phases of hypothalamo-pituitary–adrenal activity. Crucial to the understanding is the fact that corticosteroids bind to two types of receptors, one that is activated already under rest, and another that mostly comes into play when hormone levels rise e.g. after stress. Activation of the respective receptors results in completely different effects on cell physiology. This explains why corticosterone can affect limbic cells (which mostly express both receptor types) in opposite directions, depending on the hypothalamo-pituitary–adrenal activity. A second important step was the observation that corticosterone not only acts in a delayed manner, but also rapidly, so that it already plays a role (in concert with other stress hormones) shortly after stress exposure. Finally, it has become clear over the past years that corticosterone has regionally dependent effect, partly governed by the receptor distribution, but also by other factors such as the protein context of a specific cell population (see De Bosscher

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et al. in this issue). Extrapolation of findings from the CA1 area, which is presently most intensely investigated, is therefore difficult. This means that for a better understanding of corticosteroid actions on limbic brain cells it is imperative to also investigate nongenomic and genomic cellular effects in areas outside of the hippocampus that play an important role in behavioral adaptation, such as the amygdala nuclei, the lateral septum and the prefrontal cortex. How the brain responds to a stressor and corticosteroids also depends on the life history of the organism. This is illustrated by the findings on chronic stress. Hippocampal cells respond very differently to a rise in corticosteroid level when there is a history of chronic stress than without such a history. There is evidence that this is also the case with regard to early life history. For instance, maternal deprivation at postnatal day 3 results in attenuation of serotonin responses in adult CA1 hippocampal neurons; the attenuation is very comparable to the effect of prolonged stress in adulthood (Van Riel et al., 2004). Another well-documented example concerns the effect of maternal care during the first weeks of life. Animals which received relatively little care display prolonged exposure to corticosterone upon stress in adulthood compared to offspring from mothers which spend more time with their litters (for review Meaney, 2001). The former group is also impaired in spatial learning. Preliminary data indicate that LTP in the CA1 area is largely impaired in the low-care compared to the high-care offspring (Champagne et al., 2006). Despite the realization that chronic stress leads to substantial changes in neuronal function, many aspects are still unresolved. At present, it is entirely unclear how several weeks of stress change basal CA1 neuronal function. Which transmitters and hormones play a role? The effectiveness of treatment with a glucocorticoid receptor antagonist supports the involvement of glucocorticoid receptors. However, other compounds also have shown beneficial effects, especially with respect to prevention of morphological changes and suppression of neurogenesis after chronic stress. Are cellular changes after chronic stress caused by a slow additive effect? Does the state of neurons that occurs after a single stress slowly become fixed? This may hold true for some phenomena –like the impairment in LTP induction or increased calcium influx– but not for all: The most conspicuous example is the response to serotonin, where acute stress exerts effects opposite to those seen after chronic stress. Also the strong response to elevated corticosteroid levels against a background of chronic stress, as seen particularly in dentate neurons but also in the amygdala, is not quite understood. The available data do not indicate that glucocorticoid receptors are markedly higher expressed in these areas after chronic stress. But there are many alternative ways in which stronger glucocorticoid receptor function can be achieved, e.g. through modulation of co-activators or -repressors, or of transcription factors through which glucocorticoid receptors repress gene transcription. This review describes effects of corticosteroid hormones in the limbic system, at the level of single cells or groups of cells (field potentials, LTP). From there implications for behavioral function are inferred. However, at present these are mere spec-

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