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Exposure to stress during the early postnatal period (i.e., early life stress, ES) can impact brain physiology and modify individual variability in adult social behavior. Arginine vasopressin (AVP) and oxytocin (OXT) are two centrally released neuropeptides that are involved in shaping essential social behaviors, like aggression, social recognition, and social motivation. AVP and OXT modulate activity in brain regions important for the establishment of social behavior, and may be particularly sensitive to ES. In this review, we discuss whether ES alters the characteristics of the AVP- and OXT- systems in rodents, and whether these changes are associated with later alterations in aggression, social recognition, and social motivation. We have integrated causal studies indicating that (1) ES affects AVP/OXT, and (2) that changing AVP/OXT in affected regions alters social behavior. Although there is encouraging evidence that ES causes AVP- and OXT-system changes, and that these may mediate social behavior, a comprehensive understanding of the exact nature of AVP- and OXT changes and whether they are causal in establishing these behavioral disturbances needs further investigation. As there are indications that ES alters AVP- and OXT characteristics in humans as well, and that these may interact with adult predisposition to psychopathology with social dysfunction, future rodent studies may lay ground for a better understanding of such changes in humans. Ultimately, this may assist in developing therapeutic strategies to target ES effects on social behavior.

Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

Early-life stress is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of early-life stress on anxiety and memory in adulthood. We found that early-life stress increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of early life stress on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice.

After stress, circulating levels of stress hormones such as corticosterone are markedly increased. This will have an impact on the neurophysiology of limbic neurons that highly express corticosteroid receptors. Over the past decades several principles about the neurophysiological impact of corticosterone have emerged. First, corticosterone can quickly raise the excitability of hippocampal CA1 neurons shortly after stress exposure, via a nongenomic pathway involving mineralocorticoid receptors presumably located in the pre- as well as postsynaptic membrane. At the same time, gene-mediated actions via the glucocorticoid receptor are started which some hours later will result in enhanced calcium influx and impaired ability to induce long-term potentiation. These delayed actions are interpreted as a means to slowly normalize hippocampal activity and preserve information encoded early on after stress. Second, the full spectrum of neurophysiological actions by corticosterone is accomplished in interaction with other stress mediators, like noradrenaline. Third, these effects in the CA1 hippocampal region cannot be generalized to other brain regions such as the basolateral amygdala or paraventricular nucleus: There seems to be a highly differentiated response, which could serve to facilitate neuroendocrine/cognitive processing of some aspects of stress-related information, but attenuate other aspects. Finally, the time- and region-specific corticosteroid actions strongly depend on the individual's life history.

In normal life, organisms are repeatedly exposed to brief periods of stress, most of which can be controlled and adequately dealt with. The presently available data indicate that such brief periods of stress have little influence on the shape of neurons or adult neurogenesis, yet change the physiological function of cells in two time-domains. Shortly after stress excitability in limbic areas is rapidly enhanced, but also in brainstem neurons which produce catecholamines; collectively, during this phase the stress hormones promote focused attention, alertness, vigilance and the initial steps in encoding of information linked to the event. Later on, when the hormone concentrations are back to their pre-stress level, gene-mediated actions by corticosteroids reverse and normalize the enhanced excitability, an adaptive response meant to curtail defense reactions against stressors and to enable further storage of relevant information. When stress is experienced repetitively in an uncontrollable and unpredictable manner, a cascade of processes in brain is started which eventually leads to profound, region-specific alterations in dendrite and spine morphology, to suppression of adult neurogenesis and to inappropriate functional responses to a brief stress exposure including a sensitized activation phase and inadequate normalization of brain activity. Although various compounds can effectively prevent these cellular changes by chronic stress, the exact mechanism by which the effects are accomplished is poorly understood. One of the challenges for future research is to link the cellular changes seen in animal models for chronic stress to behavioral effects and to understand the risks they can impose on humans for the precipitation of stress-related disorders.

Calcium entering the cell via different routes, e.g.,N-methyl-D-aspartate (NMDA) receptors or voltage-dependent calcium channels (VDCCs), plays a pivotal role in hippocampal synaptic potentiation. Since corticosteroid hormones have been reported to enhance calcium influx through VDCCs, one may predict that these hormones facilitate hippocampal synaptic efficacy. Surprisingly, though, stress and corticosteroids have so far been found to reduce synaptic potentiation. Here, we addressed this apparent paradox and examined synaptic potentiation in the CA1 area of hippocampal slices from mice with low basal corticosterone levels 1-4 h after a brief in vitro administration of corticosterone. Nifedipine and APV were used to isolate NMDA receptor-mediated and VDCC-mediated long-term potentiations (LTPs), respectively. We report that corticosterone facilitates synaptic potentiation that depends on activation of VDCCs while impairing synaptic plasticity that is mediated by NMDA receptor activation. The glucocorticoid-receptor (GR) antagonist RU 38486 blocked both the effects of corticosterone. These results indicate that the net effect of corticosteroid hormones on synaptic plasticity is determined by the balance between different types of potentiation, a balance that may be region specific and depends on the experimental conditions. We speculate that these opposite effects on synaptic efficacy are involved in the bidirectional modulation of cognitive performance by corticosteroid hormones. (c) 2005 Wiley-Liss, Inc

Corticosterone and exposure to stressful experiences have been reported to decrease hippocampal synaptic plasticity, in particular when relatively mild stimulation paradigms-presumably activating predominantly N-methyl-d-aspartate receptors-are being used. Using various stimulation paradigms and pharmacological approaches we tested therefore the hypothesis that elevated corticosterone levels, by activating glucocorticoid receptors, predominantly hamper N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro. To address this, mouse hippocampal slices were treated for 20 min with corticosterone (100 nM) or vehicle and synaptic efficacy was examined 1-6 h later. First, we found that primed burst potentiation and synaptic potentiation after 10 Hz stimulation are predominantly N-methyl-D-aspartate receptor dependent, and are significantly suppressed after corticosterone treatment. Second, these latter effects were prevented by treating slices with the glucocorticoid receptor antagonist mifepristone prior to and during corticosterone administration. Third, theta burst potentiation, which was shown to involve activation of both N-methyl-D-aspartate receptors, voltage-dependent calcium channels and possibly other mechanisms, was not affected by corticosterone. However, theta-burst potentiation in the presence of nifedipine-singling out primarily the N-methyl-D-aspartate receptor dependent component-was reduced by corticosterone. These results indicate that corticosterone, via glucocorticoid receptor activation, selectively hampers N-methyl-D-aspartate receptor dependent synaptic plasticity in vitro and leaves more complex forms of long term potentiation unaffected. We speculate that these effects are involved in the impairment of cognitive performance by corticosteroid hormones after exposure to stressful and traumatic experiences.

Elevation of circulating corticosterone levels, either through exogenous administration of the hormone or following stress exposure, is known to reduce hippocampal synaptic potentiation in rodents. It is presently debated whether this reduction is due to activation of hippocampal glucocorticoid receptors or is primarily caused in other brain structures projecting to the hippocampus. To address this issue, we examined whether synaptic potentiation in hippocampal slices from mice with low basal corticosterone levels was altered 1-4 h after a brief in vitro administration of 100 nM corticosterone. Population spike and field excitatory postsynaptic potential (fEPSP) were recorded in the cell and dendritic layers, respectively, of the CA1 area, in response to Schaffer collateral/commissural fiber stimulation. Basal characteristics of the stimulus-response relationship were not affected by corticosterone treatment, except that after corticosterone treatment the maximal fEPSP slope was reduced while the excitability ratio was increased. For studies on potentiation of the fEPSP and population spike, stimulus intensities were chosen to evoke half maximal responses before potentiation; this intensity was significantly lower for the fEPSP than for the population spike. Primed burst potentiation of the fEPSP but not population spike was significantly attenuated after corticosterone treatment. When using a more rigorous stimulation paradigm, i.e. theta burst potentiation, synaptic potentiation was not affected by corticosterone. Raising corticosterone levels in mice by exposure to a psychosocial stressor led to comparable results in subsequent in vitro experiments; stress reduced primed burst potentiation only of the fEPSP. These data support that corticosterone affects synaptic potentiation in the mouse via direct activation of hippocampal glucocorticoid receptors but only when using mild stimulation conditions.

Genetic disruption of calmodulin-dependent protein kinase II (CaMKII) function alters hippocampal synaptic plasticity and memory in mice. We used transgenic mice carrying a tetracycline-regulated, calcium-independent form of CaMKII (CaMKII-Asp286) to investigate the role of CaMKII activation on synaptic plasticity and behavior. Mice expressing low levels of a CaMKII-Asp286 transgene have facilitated low-frequency (5 Hz)-induced long-term potentiation (LTP), whereas mice with high levels of transgene expression have a deficit in this form of plasticity. Behavioral impairments on fear-conditioned memory and visible water maze correlate with the level of CaMKII-Asp286 expression. Mice with high levels of CaMKII-Asp286 have reversible, compensatory changes in the expression of genes associated with inhibitory neurotransmission. These results demonstrate that in the hippocampus, CaMKII activation facilitates the induction of low-frequency LTP, but at high levels of expression, compensatory mechanisms act to inhibit the induction of this form of LTP. The most severe behavioral impairments are associated with activation of this compensatory mechanism.

Upon exposure to stressful experiences, steroid hormones, neurotransmitters, and neuromodulators are released which modulate specific processes in the brain. While the release of these compounds is believed to promote behavioral adaptation to stressful experiences, they have also been implicated in stress-related psychopathology. Extensive research in the past decade has culminated in a deeper understanding of the cellular and molecular mechanisms of how stress hormones, neurotransmitters, and neuromodulators, alone and in concert, affect the brain. This new multidisciplinary approach involving behavioral, electrophysiological, molecular, and epigenetic studies is used to elucidate the long-lasting complex effects of stress on cognitive functions in the brain. The target for the action of these mediators ranges from membrane receptors to nuclear receptors, often specific for different brain areas, affecting eventually homeostatic and various cognitive functions. In this Frontier Research Topic, we have put together chapters written by leaders in the field that provide up-to-date summaries of the different angles of work on the effects of steroid hormones, neurotransmitters, and neuromodulators on synaptic transmission and plasticity from ion channels to pathophysiological processes. The different chapters deal with epigenetics (Hunter, 2012), which details the different nuclear targets for the long-term effects of stress. Mody and Maguire (2012) discuss the role of GABA in the feedback regulation of steroid action, Levy and Tasker summarize the current knowledge on the regulation of the HPA axis (Levy and Tasker, 2012). The main section of the Frontier Topic involves novel views on postsynaptic effects of steroid hormones, CRH, and noradrenaline on synaptic functions in the brain. These include a section on amygdala-hippocampus interaction (Li and Richter-Levin, 2012), cellular, and molecular studies on CRH effects in the hippocampus (Chen et al., 2012), effects of early life stress on metabolic functions in the brain (Bock et al., 2012), interactions between noradrenaline and corticosterone on brain function (Krugers et al., 2012), region selective effects of corticosterone in the hippocampus (Maggio and Segal, 2012), and finally, effects of corticosterone on NMDA receptor function in the hippocampus (Tse et al., 2012). Finally, a behavioral study on the interaction between gestational and adult stress (Walf and Frye, 2012) concludes the list. Altogether, these papers provide state-of-the-art insights how stress determines cellular and network function and ultimately how stress affects cognition and emotion in the brain, a subject of increasing importance in modern society.

One of the core reactions in response to a stressful situation is the activation of the hypothalamus–pituitary–adrenal (HPA) axis which increases the release of glucocorticoid hormones from the adrenal glands. In concert with other neuro-modulators, such as (nor)adrenaline, these hormones enable and promote cognitive adaptation to stressful events. Recent studies have demonstrated that glucocorticoid hormones and noradrenaline, via their receptors, can both rapidly and persistently regulate the function of excitatory synapses which are critical for storage of information. Here we will review how glucocorticoids and noradrenaline alone and in synergy dynamically tune these synapses in the hippocampus and amygdala, and discuss how these hormones interact to promote behavioral adaptation to stressful situations.

Memories for emotionally arousing and fearful events are remembered well in general. This memory enhancing effect is mediated by stress hormones which are released during and shortly after exposure to the events and reflects a highly adaptive process that enables the retention of relevant information. However, in susceptible individuals, exposure to stressful events may result in post-traumatic stress disorder (PTSD) where traumatic memories are vividly expressed. Stress also has an important influence on the brain throughout the lifespan. For instance, stress during the early postnatal period impairs spatial learning and memory processes but enhances emotional memory formation later in life. Prolonged exposure to corticosteroids is also thought to promote hippocampal aging and the onset of Alzheimer’s disease. Understanding how stress affects memory is therefore crucial to understand the development of stress-related psychopathology. In this chapter, mechanisms that underlie the effects of (early life) stress on memory formation as well as potential approaches to target the effects of stress on memory formation will be addressed.

Memories for emotionally arousing and fearful events are generally well retained. From the evolutionary point of view this is a highly adaptive behavioral response aimed to remember relevant information. However, fearful memories can also be inappropriately and vividly (re)expressed, such as in posttraumatic stress disorder (PTSD). The memory formation of emotionally arousing events is largely modulated by hormones, peptides and neurotransmitters which are released during and after exposure to these conditions. One of the core reactions in response to a stressful situation is the rapid activation of the autonomic nervous system (ANS), which results in the release of norepinephrine in the brain. In addition, stressful events stimulate the hypothalamus–pituitary–adrenal (HPA) axis which slowly increases the release of glucocorticoid hormones from the adrenal glands. Here we will review how glucocorticoids and norepinephrine regulate the formation of fearful memories in rodents and humans and how these hormones facilitate the storage of information by regulating excitatory synapses.

The acquisition and consolidation of memories of stressful events is modulated by glucocorticoids, a type of corticosteroid hormone that is released in high levels from the adrenal glands after exposure to a stressful event. These effects occur through activation of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). The molecular mechanisms that underlie the effects of glucocorticoids on synaptic transmission, synaptic plasticity, learning and memory have recently begun to be identified. Glucocorticoids regulate AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptor trafficking — which is crucially involved in synaptic transmission and plasticity — both rapidly and persistently. Stress hormones may, through modulation of AMPA receptor function, promote the consolidation of behaviourally relevant information.

Humans and rodents retain memories for stressful events very well. The facilitated retention of these memories is normally very useful. However, in susceptible individuals a variety of pathological conditions may develop in which memories related to stressful events remain inappropriately present, such as in post-traumatic stress disorder. The memory enhancing effects of stress are mediated by hormones, such as norepinephrine and glucocorticoids which are released during stressful experiences. Here we review recently identified molecular mechanisms that underlie the effects of stress hormones on synaptic efficacy and learning and memory. We discuss AMPA receptors as major target for stress hormones and describe a model in which norepinephrine and glucocorticoids are able to strengthen and prolong different phases of stressful memories.

International audience; BACKGROUND: The stress hormone corticosterone has the ability both to enhance and suppress synaptic plasticity and learning and memory processes. However, until today there is very little known about the molecular mechanism that underlies the bidirectional effects of stress and corticosteroid hormones on synaptic efficacy and learning and memory processes. In this study we investigate the relationship between corticosterone and AMPA receptors which play a critical role in activity-dependent plasticity and hippocampal-dependent learning. METHODOLOGY/PRINCIPAL FINDINGS: Using immunocytochemistry and live cell imaging techniques we show that corticosterone selectively increases surface expression of the AMPAR subunit GluR2 in primary hippocampal cultures via a glucocorticoid receptor and protein synthesis dependent mechanism. In agreement, we report that corticosterone also dramatically increases the fraction of surface expressed GluR2 that undergo lateral diffusion. Furthermore, our data indicate that corticosterone facilitates NMDAR-invoked endocytosis of both synaptic and extra-synaptic GluR2 under conditions that weaken synaptic transmission. CONCLUSION/SIGNIFICANCE: Our results reveal that corticosterone increases mobile GluR2 containing AMPARs. The enhanced lateral diffusion properties can both facilitate the recruitment of AMPARs but under appropriate conditions facilitate the loss of synaptic AMPARs (LTD). These actions may underlie both the facilitating and suppressive effects of corticosteroid hormones on synaptic plasticity and learning and memory and suggest that these hormones accentuate synaptic efficacy.

Removal of adrenal hormone corticosterone in rats aged 3-4 months results within 3 days in acceleration of apoptosis and proliferation of newborn cells in the dentate gyrus (DG). A critical question is whether such a shift in the maturity of dentate cells after adrenalectomy (ADX) affects synaptic plasticity. To address this question, male rats were adrenalectomized and synaptic potentiation was recorded in vitro in hippocampal slices, as well as in vivo, in response to high frequency stimulation of the perforant path, 3 days after ADX. At this time-point, cell loss was assessed and proliferation was examined. Based on two independent parameters, bromodeoxyuridine and Ki-67, we found that removal of the adrenal glands increases proliferation rate. This increase in proliferation was, in particular, evident in those animals that displayed substantial cell loss. The accelerated cell-turnover after ADX was accompanied by reduced synaptic potentiation, both when recorded in vitro and in vivo. Corticosterone replacement in vivo (in adrenalectomized animals), at levels that activate the mineralocorticoid receptor, prevented ADX-induced proliferation, apoptosis, and restored synaptic potentiation to control levels. Importantly, corticosterone applied to slices from adrenalectomized rats also normalized synaptic potentiation, despite increased proliferation. This suggests that changes in cell proliferation and apoptotic cell death in the DG are not necessarily key factors determining the efficacy of synaptic potentiation.

Prolonged exposure to stressful events has been reported to inhibit the ability of hippocampal synapses to increase their synaptic efficacy. Here we tested if these effects could be prevented by blocking activation of glucocorticoid receptors during the last 4 days of the stress paradigm. In order to address this question, animals were exposed to 21 days of variable and inescapable stressors. Handled animals served as controls. During the last 4 days of the stress regime, animals were treated with the glucocorticoid receptor antagonist RU486. We found that 1 day after the last stressor, synaptic plasticity in the CA1 area of hippocampal slices is impaired in chronically stressed animals. Importantly, treating chronically stressed animals with RU486 for 4 days completely prevented this decrease in synaptic potentiation; RU486 treatment of handled controls did not affect potentiation. Treating hippocampal slices from control animals with high levels of corticosterone also impaired synaptic plasticity; this effect was similar for untreated and RU486-treated animals. Treating slices from chronically stressed animals with corticosterone did not further decrease synaptic plasticity. These data indicate that 4 days blockade of the glucocorticoid receptor, during a stress regime, is sufficient to fully restore synaptic plasticity.

This chapter highlights the current views on corticosteroid modulation of amino acid-mediated transmission. Amino acids such as glutamate or 3,-amino butyric acid (GABA) are responsible for most of the excitatory and inhibitory transmission in brain. By targeting these systems, corticosteroid hormones could alter information processing in a very effective way. So far, data were mostly collected in the rodent hippocampus, which expresses mineralo- as well as glucocorticoid receptors. In general, occupation of mineralocorticoid receptors is found to be necessary to maintain neuronal integrity, stable amino acid-mediated transmission and synaptic potentiation. In the CA1 area, additional activation of glucocorticoid receptors suppresses amino acid-mediated responses to synaptic stimulation, administered either with low-frequency (basal transmission) or with high-frequency patterns. Probably, glutamate as well as GABA-mediated responses are suppressed. Effects were usually reported for high doses of the hormone, found to be relatively fast in onset and are thus possibly caused by a nongenomic pathway. Mild stressors affected amino acid transmission in the hippocampus in vivo similarly as corticosteroid administration in vitro, although it is not clear (i) whether the in vivo effects are partly due to an altered availability of the amino acids – e.g., by changes in release or uptake –, (ii) whether these effects can be exclusively ascribed to stress-induced rise in corticosteroid hormones, and (iii) to what extent relay of areas other than the hippocampus is involved. Chronic stress was found to raise the glutamate-mediated transmission in all hippocampal subareas, albeit caused by regionally different mechanisms. Functional changes in amino acid-mediated pathways in other brain regions have been much less investigated, although recent data indicate that moderately high doses of corticosterone suppress GABAergic innervation of parvocellular neurons in the hypothalamic paraventricular nucleus, the key site for regulation of hypothalamo–pituitary–adrenal activity. Although amino acid projections (and functional processes depending on them) clearly seem to be modulated by corticosteroid hormones and stress, the mechanism underlying this modulation is virtually unknown. Future studies will need to clarify the signaling pathways underlying corticosteroid effects on amino acid transmission and will have to address the functional consequences for behavioral processes.

Elimination of corticosteroids after ischemia, by removal of the adrenals, has been reported to preserve neuronal integrity later. To establish the therapeutic potential of this observation, the authors address two questions: first, whether clinically more relevant steroid manipulations after ischemia exert similar protective effects, and second, whether changes in synaptic functioning occur along with structural alterations. To test this, the authors treated animals immediately after hypoxia-ischemia with (1) the steroid synthesis inhibitor metyrapone, (2) the synthetic glucocorticoid receptor agonist dexamethasone, (3) the selective glucocorticoid antagonist RU 38486, or (4) corticosterone. Metyrapone, but none of the other compounds, attenuated the occurrence of seizures immediately after ischemia. Twenty-four hours after hypoxia-ischemia, CAI hippocampal field potentials in response to stimulation of Schaffer/commissural fibers were found to be reduced. The attenuation of synaptic transmission was partly prevented by metyrapone. None of the other experimental treatments influenced the impaired synaptic function. Gross morphologic analysis revealed no differences in the loss of neuronal structure between the experimental groups at this time point. Taken together, these data suggest that metyrapone preserves neuronal functioning despite loss of neuronal structure. The authors tentatively conclude that preventing the ongoing production of steroids shortly after ischemia can delay and attenuate the appearance of ischemia-related pathology.

In mice with a homozygous or heterozygous deficiency for ApoE as well as in wild-type animals we established synaptic responsiveness in the hippocampal CA1 area following stimulation of the Schaffer/commissural fibers. The maximal population spike amplitude was significantly larger in wild-type animals than in mice lacking the ApoE gene, whereas the facilitation in population spike amplitude after paired pulse stimulation was most pronounced in homozygous mutant mice. Primed burst stimulation induced a lasting increase in population spike amplitude of all three groups. Apart from a more pronounced initial potentiation in the homozygous mutants, primed burst potentiation was comparable in all groups. Subsequent theta burst stimulation resulted in a long-term enhanced synaptic responsiveness which was impaired in heterozygous animals. The data show that both homo- and heterozygous ApoE mutant mice display altered synaptic plasticity in the hippocampal CA1 area.