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Binding information to the context in which It is perceived promotes the recognition of information when later presented in the same context (contextualization). This is stronger for neutral than emotional content, since the latter distracts subjects from forming a link. We hypothesized that the ability to contextualize information under stressful conditions may protect individuals from generalization and hence render them more resilient to developing PTSD in the face of trauma. To test this, healthy male (human) subjects were first exposed to a contextualization test, 30 or 210 min after exogenous delivery of hydrocortisone (or placebo). Rapid and late hydrocortisone effects suppressed and enhanced respectively contextualization of emotional content. Contextualization of neutral content remained unaffected. Next, we tested individuals for contextualization directly or 2 hrs after psychoscial stress. Neutral conditions were more contextualized 2 hrs (than directly) after stress, while there was no effect for emotional content. A similar discrepancy between stress and hydrocortisone delivery was earlier observed in relation to intertemporal choice, indicating that cortisol may contribute to but cannot be equated to stress-related consequences on cognition. To examine the predictive value of contextualization for the vulnerability to PTSD, we reverted to a rat model, in which post-trauma PTSD-like behavior was observed in ~20% of the subjects. As predicted, pre-trauma contextualization inversely correlated with post-trauma PTSD-like behavior, but only in the non-stress group. These findings highlight the importance of contextualization in relation to stress and trauma but also emphasize differences between hydrocortisone administration and stress in humans and rodents. [ABSTRACT FROM AUTHOR]

Rapid non-genomic effects of corticosteroid hormones, affecting glutamatergic and GABAergic transmission, have been described for many limbic structures in the rodent brain. These rapid effects appear to be region specific. It is not always clear which (or even whether) corticosteroid receptor -the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR)- initiate these rapid effects. In the hippocampus and amygdala membrane-associated MR, but also membrane-associated GR (in amygdala), are involved. Other studies indicate that the rapid modulation may be induced by transactivation of kinases, or other receptors, like the G-protein coupled estrogen receptor (GPER) which was recently found to bind the mineralocorticoid aldosterone. In the current study we explored, in young adult male C57Bl6 mice, possible rapid effects of corticosterone on layer 2/3 infralimbic-prefrontal cortex (IL-PFC) neurons. We show that corticosterone, via non-genomic MR activation, reduces the mEPSC -but does not affect mIPSC- frequency; we observed no effect on mEPSC or mIPSC amplitude. As a result, overall spontaneous activity in the IL-PFC is suppressed. A potential role of GPER cannot be excluded, since G-15, an antagonist of GPER, also prevented the rapid effects of corticosterone. [ABSTRACT FROM AUTHOR]

Exposure to early-life adversity may program brain function to prepare individuals for adaptation to matching environmental contexts. In this study we tested this hypothesis in more detail by examining the effects of early-life stress – induced by raising offspring with limited nesting and bedding material from postnatal days 2–9 – in various behavioral tasks and on synaptic function in adult mice. Early-life stress impaired adult performance in the hippocampal dependent low-arousing object-in-context recognition memory task. This effect was absent when animals were exposed to a single stressor before training. Early-life stress did not alter high-arousing context and auditory fear conditioning. Early-life stress-induced behavioral modifications were not associated with alterations in the dendritic architecture of hippocampal CA1 pyramidal neurons or principal neurons of the basolateral amygdala. However, early-life stress reduced the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and glutamate release probability specifically in hippocampal CA1 neurons, but not in the basolateral amygdala. These ex vivo effects in the hippocampus were abolished by acute glucocorticoid treatment. Our findings support that early-life stress can hamper object-in-context learning via pre- and postsynaptic mechanisms that affect hippocampal function but these effects are counteracted by acute stress or elevated glucocorticoid levels. [ABSTRACT FROM AUTHOR]

We will highlight in honor of Randall Sakai the peculiar characteristics of the brain mineralocorticoid receptor (MR) in its response pattern to the classical mineralocorticoid aldosterone and the naturally occurring glucocorticoids corticosterone and cortisol. Neurons in the nucleus tractus solitarii (NTS) and circumventricular organs express MR, which mediate selectively the action of aldosterone on salt appetite, sympathetic outflow and volume regulation. The MR-containing NTS neurons innervate limbic-forebrain circuits enabling aldosterone to also modulate reciprocally arousal, motivation, fear and reward. MR expressed in abundance in this limbic-forebrain circuitry, is target of cortisol and corticosterone in modulation of appraisal processes, memory performance and selection of coping strategy. Complementary to this role of limbic MR is the action mediated by the lower affinity glucocorticoid receptors (GR), which promote subsequently memory storage of the experience and facilitate behavioral adaptation. Current evidence supports the hypothesis that an imbalance between MR- and GR-mediated actions compromises resilience and adaptation to stress. [ABSTRACT FROM AUTHOR]

Shortly after stress, basolateral amygdala neurons are exposed to sequential yet partly overlapping waves of hormones. We examined how these hormonal waves can change activity of basolateral amygdala neurons such that emotional aspects of stress become so deeply ingrained. To this end, spontaneous glutamatergic transmission was recorded during and up to several hours after combined adrenergic and corticosteroid waves, targeting the time-window relevant for encoding of stress-related information. Hormonal waves mimicking moderately stressful conditions cause a transient enhancement followed by later suppression of glutamatergic transmission. However, this late phase flips from suppressed to enhanced glutamatergic transmission with conditions mimicking severe stress. Such a prolonged window of enhanced excitability may contribute to the excessively strong encoding seen after the experience of highly stressful or traumatic events. [ABSTRACT FROM AUTHOR]

Summary The MR is an important regulator of the hypothalamic–pituitary–adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex-dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort ( N = 665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) ( N = 1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex × maltreatment × haplotype: β = −4.07, P = 0.029) and in the clinical sample (sex × maltreatment × haplotype, β = −2.40, P = 0.011). Specifically, female individuals in the population-based sample were protected ( β = −4.58, P = 2.0e −5 ), whereas males in the clinical sample were at increased risk ( β = 2.54, P = 0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample ( β = 4.58, P = 7.5e −5 ) whereas male CG-carriers showed increased resilience in the clinical sample ( β = −2.71, P = 0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex-specific role of MR in the etiology of depression following childhood maltreatment. [ABSTRACT FROM AUTHOR]

Abstract: Stress causes the release of many transmitters and hormones, including corticosteroids. These molecules enter the brain and exert their effects through the mineralo- and glucocorticoid receptor. The former receptor plays an important role in neuronal stability. However, it also mediates rapid non-genomic corticosteroid effects that in synergy with other stress mediators activate limbic cells and promote behavioral choices allowing the organism to quickly respond to the imminent danger. Glucocorticoid receptors primarily mediate slow genomic effects, for instance in the hippocampus and prefrontal cortex, which are thought to contribute to contextual and higher cognitive aspects of behavioral performance several hours after stress. Rapid and slow effects interact and collectively contribute to successful behavioral adaptation. Long-term disturbances in the release pattern of corticosteroid hormones and in the responsiveness of their receptors give rise to structural and functional changes in neuronal properties which may contribute to the expression of psychopathology. [Copyright &y& Elsevier]

Abstract: It is well known that stressful experiences may affect learning and memory processes. Less clear is the exact nature of these stress effects on memory: both enhancing and impairing effects have been reported. These opposite effects may be explained if the different time courses of stress hormone, in particular catecholamine and glucocorticoid, actions are taken into account. Integrating two popular models, we argue here that rapid catecholamine and non-genomic glucocorticoid actions interact in the basolateral amygdala to shift the organism into a ‘memory formation mode’ that facilitates the consolidation of stressful experiences into long-term memory. The undisturbed consolidation of these experiences is then promoted by genomic glucocorticoid actions that induce a ‘memory storage mode’, which suppresses competing cognitive processes and thus reduces interference by unrelated material. Highlighting some current trends in the field, we further argue that stress affects learning and memory processes beyond the basolateral amygdala and hippocampus and that stress may pre-program subsequent memory performance when it is experienced during critical periods of brain development. [Copyright &y& Elsevier]

Abstract: Corticosteroid hormones, which are released in high amounts after stress, easily pass the blood–brain-barrier. In the brain they bind to intracellular receptors which act as transcriptional regulators. These receptors are highly expressed in neurons of the hippocampal formation and the amygdala, areas that play a role in (emotional) memory formation. Voltage gated Ca2+ channels are among the most prominent targets of corticosteroid hormones. When the levels of corticosterone - the prevalent corticosteroid in rats and mice- are low, L-type Ca2+ currents of CA1 hippocampal cells are small. However, when hormone levels rise e.g. after stress, the amplitude of L-type Ca2+ currents will be slowly enhanced, through a process requiring DNA binding of glucocorticoid receptor homodimers. Kinetic properties and voltage dependency of the currents remain unchanged. Neurons in the basolateral amygdala respond in a comparable fashion, but Ca2+ currents of neurons in the dentate gyrus are unaffected by corticosteroids. The stress-induced increase in Ca2+ influx has considerable functional consequences in health and disease. At the short term, i.e. 1–4h after stress, the enhanced Ca2+ influx contributes to stronger firing frequency accommodation and a higher threshold for the induction of long-term potentiation. This helps to normalize neuronal activity after stress and presumably protects earlier encoded, stress-related information. At the longer term, though, increased Ca2+ load may impose a risk, increasing the vulnerability of limbic cells to additional challenges e.g. during epileptic or ischemic episodes. [Copyright &y& Elsevier]

Stressful events activate the amygdala and a network of associated brain regions. Studies in both humans and rodents indicate that noradrenaline has a prominent role in this activation. Noradrenaline induces a hypervigilant state that helps to remember the event. This mnemonic effect is enhanced when the situation is so stressful that substantial amounts of corticosteroids are released and reach the amygdala. The combination of the two hormones leads to optimal strengthening of contacts and thus memory. Yet, rises in corticosteroid levels that are not precisely synchronized with noradrenaline release do not act synergistically but rather prevent or suppress the effect of noradrenaline. This dynamic interaction illustrates the adaptive and potentially protective capacity of corticosteroids regarding traumatic memories. [Copyright &y& Elsevier]

Summary: Exposure to stressful situations activates two hormonal systems that help the organism to adapt. On the one hand stress hormones achieve adaptation by affecting peripheral organs, on the other hand by altering brain function such that appropriate behavioral strategies are selected for optimal performance at the short term, while relevant information is stored for reference in the future. In this chapter we describe how cellular effects induced by stress hormones – in particular by glucocorticoids – may contribute to the behavioral outcome after a single stressor. In addition to situations of acute stress, chronic uncontrollable and unpredictable stress also exerts profound effects on structure and function of limbic neurons. The impact of chronic stress is not a mere cumulative effect of what is seen after acute stress exposure. Dendritic trees are expanded in some regions but reduced in others. In general, cells are exposed to a higher calcium load upon depolarization, but show attenuated responses to serotonin. Synaptic strengthening is largely impaired. In this viewpoint we speculate how cellular effects after chronic stress may be maladaptive and could contribute to the development of psychopathology in genetically vulnerable individuals. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Summary: In this review, studies on the role of glucocorticoids during brain development are recapitulated with reference to their immediate effects and long-term impact on central functions. Traditionally, this research has focused on detrimental consequences of stress and exogenous glucocorticoid exposure but far less on the ability to develop resilience to stress despite exposure to early adversity. Recent findings suggest that the impact of early life conditions turns out as either harmful or protective depending on later environmental context. To explain this, the concept of ‘predictive adaptive response’ was introduced, implying that early-life conditions may prepare for life ahead through glucocorticoid programming and phenotypic plasticity with the goal to ‘match’ future environmental demands. This concept has led to the hypothesis that a ‘mismatch’ between early and later life conditions can enhance vulnerability to disease. [Copyright &y& Elsevier]

Corticosteroids – secreted after stress – have profound effects on brain and behavior. These effects are mediated by mineralocorticoid and glucocorticoid receptors, which are abundantly expressed in limbic neurons. The role of mineralocorticoid receptors in higher brain functions has never been well understood. Here we argue that the recently discovered low-affinity membrane version of the mineralocorticoid receptor contributes to the initial phase of the stress reaction; this is complemented by the glucocorticoid receptor which terminates the stress response. This concept may explain why human carriers of a mineralocorticoid receptor gene variant display enhanced neuroendocrine and autonomic responsiveness to a psychological stressor. [Copyright &y& Elsevier]

The existence of U-shaped dose dependencies has been known for a long time. With regard to corticosteroid action in brain cells, a dual receptor system that works in opposing directions can explain the occurrence of a U-shaped dose dependency. However, recent evidence indicates that many cell- and tissue-specific factors (e.g. the local availability of corticosterone, the expression of receptor variants and the cellular content of other proteins and molecules) also determine the effectiveness of the hormone. This could result in dose dependencies with a different shape, despite the local presence of two receptor types. [Copyright &y& Elsevier]

The effects of stress on learning and memory are not always clear: both facilitating and impairing influences are described in the literature. Here we propose a unifying theory, which states that stress will only facilitate learning and memory processes: (i) when stress is experienced in the context and around the time of the event that needs to be remembered, and (ii) when the hormones and transmitters released in response to stress exert their actions on the same circuits as those activated by the situation, that is, when convergence in time and space takes place. The mechanism of action of stress hormones, particularly corticosteroids, can explain how stress within the context of a learning experience induces focused attention and improves memory of relevant information. [Copyright &y& Elsevier]

Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus. Biotinylated-oligonucleotide immunoprecipitation in primary hippocampal neurons reveals that MR binding, rather than GR binding, to the Fkbp5 gene regulates FKBP5 expression during baseline activity of glucocorticoids. Notably, FKBP5 and MR exhibit similar hippocampal expression patterns in mice and humans, which are distinct from that of the GR. Pharmacological inhibition and region- and cell type-specific receptor deletion in mice further demonstrate that lack of MR decreases hippocampal Fkbp5 levels and dampens the stress-induced increase in glucocorticoid levels. Overall, our findings demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR sensitivity to glucocorticoids, providing insight into mechanisms of stress homeostasis. [Display omitted] • FKBP5 and MRs, but not GRs, exhibit similar hippocampal expression patterns • MRs, rather than GRs, regulate FKBP5 expression in hippocampal neurons at baseline • Inhibition and deletion of MRs decrease hippocampal Fkbp5 mRNA levels in vivo • Forebrain MR deletion leads to GR hypersensitivity during acute stress Hartmann et al. demonstrate that MRs regulate baseline FKBP5 expression in the hippocampus. This regulation leads to a modification of GR sensitivity to glucocorticoids during acute stress. The results suggest that FKBP5 acts as a key modulator of HPA axis activity by mediating the fine-tuning of hippocampal MR:GR balance. [ABSTRACT FROM AUTHOR]

One of the features of the Consortium on Individual Development is the existence of a rodent cohort, in parallel with the human cohorts. Here we give an overview of the current status. We first elaborate on the choice of rat and mouse models mimicking early life adverse or beneficial conditions during development. We performed a systematic literature search on early life adversity and adult social behavior to address the status quo. Next, we describe the behavioral tasks we used and designed to examine behavioral control and social competence in rodents. The results so far indicate that manipulation of the environment in the first postnatal week only subtly affects social behavior. Stronger effects were seen in the model that targeted early adolescence; once adult, these rats are characterized by increased attention, a higher degree of impulsiveness and reduced social interest in peers. Many experiments in our rodent models with tightly controlled conditions were inspired by findings in human cohorts, and now allow in-depth mechanistic investigations. Vice versa, some of the findings in rodents are currently followed up by dedicated investigations in the human cohorts. This exemplifies the added value of animal investigations in a consortium encompassing primarily human developmental cohorts. [ABSTRACT FROM AUTHOR]

In this study, we aimed to develop a behavioral task that measures pro-social decision making in rats. A fully automated, operant pro-social two-choice task is introduced that quantifies pro-social preferences for a mutual food reward in a set-up with tightly controlled task contingencies. Pairs of same-sex adult Wistar rats were placed in an operant chamber divided into two compartments (one rat per compartment), separated by a transparent barrier with holes that allowed the rats to see, hear, smell, but not touch each other. Test rats could earn a sucrose pellet either for themselves (own reward) or for themselves and the partner (both reward) by means of lever pressing. On average, male rats showed a 60 % preference for the lever that yielded a food reward for both themselves and their partner. In contrast, females did not show lever preference, regardless of the estrous cycle phase. Next, the impact of juvenile environmental factors on male rat social decision making was studied. Males were group-housed from postnatal day 26 onwards in complex housing Marlau™ cages that provided social and physical enrichment and stimulation in the form of novelty. Complex housed males did not show a preference for the pro-social lever. [ABSTRACT FROM AUTHOR]

An abstract of the article "Corticosteroid Hormones, Synaptic Strength and Emotional Memories: Corticosteroid Modulation of Memory: A Cellular and Molecular Perspective," by Olof Wiegert and colleagues is presented.

An abstract of the article "Role of Corticosteroid Hormones in the Dentate Gyrus," by Marian Joëls is presented.

Corticosteroid hormones, released during stressful encounters, have profound and far-reaching effects on cognition. They are often thought to accomplish these effects primarily via glucocorticoid receptors (GR), but recent findings from rodent and human studies argue for an additional, critical role of the mineralocorticoid receptor (MR) in cognitive changes in response to stress. We propose that the MR initiates rapid changes in the recruitment of specific neural systems, inducing a shift towards cognitively less-demanding processing and allowing a quick and adequate response to the situation. In combination with slower and longer-lasting actions mediated by GR, this shift leads to optimal coping with the ongoing stressful event. [ABSTRACT FROM AUTHOR]

Highlights: [•] Stress-sensitive neuromodulators exert spatially and temporally specific effects. [•] These effects may trigger shifts in functioning of large-scale networks. [•] During acute stress, neural resources are allocated to a salience processing network. [•] This effect reverses in the aftermath, promoting executive control network function. [ABSTRACT FROM AUTHOR]

Summary: Corticosteroids induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It is presently unknown how these time-dependent effects of cortisol affect fear memory of delay and trace conditioning. This distinction is of special interest because the neural substrates underlying these types of conditioning may be differently affected by time-dependent cortisol effects. Delay conditioning is predominantly amygdala-dependent, while trace conditioning additionally requires the hippocampus. Here, we manipulated the timing of cortisol action during acquisition of delay and trace fear conditioning, by randomly assigning 63 men to one of three possible groups: (1) receiving 10mg hydrocortisone 240min (slow cort) or (2) 60min (rapid cort) before delay and trace acquisition, or (3) placebo at both times, in a double-blind design. The next day, we tested memory for trace and delay conditioning. Fear potentiated startle responses, skin conductance responses and unconditioned stimulus expectancy scores were measured throughout the experiment. The fear potentiated startle data show that cortisol intake 240min before actual fear acquisition (slow cort) uniquely strengthened subsequent trace conditioned memory. No effects of cortisol delivery 60min prior to fear acquisition were found on any measure of fear memory. Our findings emphasize that slow, presumably genomic, but not more rapid effects of corticosteroids enhance hippocampal-dependent fear memories. On a broader level, our findings underline that basic experimental research and clinically relevant pharmacological treatments employing corticosteroids should acknowledge the timing of corticosteroid administration relative to the learning phase, or therapeutic intervention. [Copyright &y& Elsevier]

Current drugs for treating schizophrenia are mostly variations on a theme that was started over 50 years ago. Sadly, clinical efficacy has not improved substantially over the years. We argue that both clinical and preclinical researchers have focused too much on psychosis, which is only one of the hallmarks of schizophrenia. This narrow focus has hampered the development of relevant animal models and human experimental medicine paradigms. Other fields in psychiatry, most notably in the realms of addiction and anxiety, have prospered from results obtained in parallel studies using animal models and experimental human studies. Lessons to be learned from those models and recent genetic and cognitive insights in schizophrenia can be utilized to develop better animal and human models and, potentially, novel treatment strategies. [ABSTRACT FROM AUTHOR]

Summary: Stress is known to differentially modulate memory function. Memory can be impaired or strengthened by stress, depending on e.g. the memory type and phase under study, the emotional value of the learned information and the sex of the subjects. Here, we addressed the latter and investigated the impact of psychosocial stress on long-term memory for neutral and emotional pictures and working memory in typical samples of male versus female students. In total, 77 subjects (54 women of which 39 used oral contraceptives) were exposed to either the Trier Social Stress Test (TSST) or a control condition, and then engaged in a long-term memory task (emotionally arousing and neutral pictures; surprise recall after one week) and a working memory (n-back) task. During the experiment salivary cortisol and alpha-amylase levels as well as subjective affect state were assessed. As expected, stress hormone concentrations as well as subjective negative affect states increased significantly in response to the stress task. Men reacted more to the stressor in terms of cortisol responses than women, probably due to oral contraceptive use of the latter. Results show that, in male as well as in female students, memory for emotional arousing information was better than for neutral information, in both the stress and control condition. Stress enhanced recognition memory for emotional versus neutral pictures only in male subjects. Moreover, stress enhanced working memory, particularly in males, during the first block of a 2-back task. The lack of stress effects on memory in women might be explained by oral contraceptive use, leading to blunted HPA-axis responses and secondary to reduced stress effects on memory. The results emphasize that stress affects both long-term and working memory differentially in male versus female students. [ABSTRACT FROM AUTHOR]

Neurogenesis and apoptosis in the hippocampal dentate gyrus (DG) occur during development and adulthood. However, little is known about how these two processes relate to each other during aging. In this study, we examined apoptosis, proliferation, migration, and survival of newborn cells in the young (2 weeks), young-adult (6 weeks), middle-aged (12 months), and old (24 months) rat DG. We also measured dentate volume and cell numbers, along with basal corticosterone and stress response parameters. We show that new cell proliferation and apoptosis slow down profoundly over this time period. Moreover, migration and differentiation into a neuronal or glial phenotype was strongly reduced from 6 weeks of age onwards; it was hardly present in middle-aged and old rats as confirmed by confocal analysis. Surprisingly, we found no correlation between cell birth and corticosterone levels or stress response parameters in any age group. [Copyright &y& Elsevier]

• Memory contextualization enables selective context-dependent retrieval. • Late , compared to early, stress-effects enhance the contextualization of neutral information. • Context-dependency of negative material is not influenced by endogenous stress response. Memories about stressful experiences need to be both specific and generalizable to adequately guide future behavior. Memory strength is influenced by emotional significance, and contextualization (i.e., encoding experiences with their contextual details) enables selective context-dependent retrieval and protects against overgeneralization. The current randomized-controlled study investigated how the early and late phase of the endogenous stress response affects the contextualization of neutral and negative information. One hundred healthy male participants were randomly divided into three experimental groups that performed encoding either 1) without stress (control), 2) immediately after acute stress (early) or 3) two hours after acute stress (late). Stress was induced via the Trier Social Stress Test and salivary alpha-amylase and cortisol levels were measured throughout the experiment. In the Memory Contextualization Task, neutral and angry faces (items) were depicted against unique context pictures during encoding. During testing 24 h later, context-dependent recognition memory of the items was assessed by presenting these in either congruent or incongruent contexts (relative to encoding). Multilevel analyses revealed that neutral information was more contextualized when encoding took place two hours after psychosocial stress, than immediately after the stressor. Results suggest that the late effects in the unique, time-dependent sequence of a healthy endogenous stress response, could complement reduced contextualization immediately after stress. The contextualization of negative information was not influenced by psychosocial stress, as opposed to earlier reported effects of exogenous hydrocortisone administration. An imbalance between the early and late effects of the endogenous stress response could increase vulnerability for stress-related psychopathology. [ABSTRACT FROM AUTHOR]

Highlights • GR-1 F methylation was not associated with an altered cortisol response to the Trier Social Stress Test (AUCi and AUCg). • GR-1 F methylation was not associated with childhood trauma. • No group differences in GR-1F methylation were observed in controls, psychiatric patients or siblings of psychiatric patients. • These results suggest that multifactorial models for stress-related psychopathology are needed. Abstract Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 1 7 region (GR-1 7 or GR-1 F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1 F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1 F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1 F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1 F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1 F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1 F methylation to be a useful parameter at an individual level. [ABSTRACT FROM AUTHOR]

Early life stress (ELS) alters the excitation-inhibition-balance (EI-balance) in various rodent brain areas and may be responsible for behavioral impairment later in life. The EI-balance is (amongst others) influenced by the switch of GABAergic transmission from excitatory to inhibitory, the so-called "GABA-switch". Here, we investigated how ELS affects the GABA-switch in mouse infralimbic Prefrontal Cortex layer 2/3 neurons, using the limited-nesting-and-bedding model. In ELS mice, the GABA-switch occurred already between postnatal day (P) 6 and P9, as opposed to P15–P21 in controls. This was associated with increased expression of the inward chloride transporter NKCC1, compared to the outward chloride transporter KCC2, both of which are important for the intracellular chloride concentration and, hence, the GABA reversal potential (Erev). Chloride transporters are not only important for regulating chloride concentration postsynaptically, but also presynaptically. Depending on the Erev of GABA, presynaptic GABA A receptor stimulation causes a depolarization or hyperpolarization, and thereby enhanced or reduced fusion of glutamate vesicles respectively, in turn changing the frequency of miniature postsynaptic currents (mEPSCs). In accordance, bumetanide, a blocker of NKCC1, shifted the Erev GABA towards more hyperpolarized levels in P9 control mice and reduced the mEPSC frequency. Other modulators of chloride transporters, e.g. VU0463271 (a KCC2 antagonist) and aldosterone -which increases NKCC1 expression-did not affect postsynaptic Erev in ELS P9 mice, but did increase the mEPSC frequency. We conclude that the mouse GABA-switch is accelerated after ELS, affecting both the pre- and postsynaptic chloride homeostasis, the former altering glutamatergic transmission. This may considerably affect brain development. • Early life stress (limited bedding and nesting model) accelerates the GABA-switch in IL-PFC neurons of male mice. • NKCC1 expression is decreased directly after early life stress. • Presynaptic Cl− concentration in the IL-PFC most likely determines the GABA A receptor mediated release of glutamate. • Overall, early life stress causes an attenuation of the excitatory tone in the mouse infralimbic prefrontal cortex. [ABSTRACT FROM AUTHOR]

Intertemporal choices – decisions involving trade-offs of outcomes at different points in time – are often made under stress. Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in the release of corticosteroids. Recent studies provide evidence that corticosteroids can induce rapid non-genomic effects focused on immediate resolution of the stressful situation, followed by slower genomic effects focused on long-term recovery after stress. It remains unknown, however, how corticosteroids affect intertemporal choice. We randomly assigned healthy men to receive either 10 mg hydrocortisone or a placebo before measuring intertemporal choice. To target time-dependent effects, hydrocortisone was administered either 195 or 15 min before choice elicitation, while a placebo was administered at the other timepoint, in a double-blind design. Intertemporal choices were elicited by offering subjects decisions between small rewards available sooner vs. large rewards available later. We demonstrate a time-dependent effect of hydrocortisone administration on intertemporal choice: when tested 15 min after hydrocortisone administration, subjects showed a strongly increased preference for the small, soon reward over the larger, delayed reward. In contrast, this effect was not found when testing occurred 195 min after hydrocortisone administration. Together, these results suggest that the physiological effects of acute, but not delayed, stress may increase temporal discounting. [ABSTRACT FROM AUTHOR]

The hypothalamus-pituitary-adrenal (HPA) axis and its end product cortisol are essential for an adequate response to stress. Considering the role of stress as a risk factor for psychiatric disorders, it is not surprising that cortisol stress reactivity has frequently been investigated in patients versus healthy individuals. However, the large heterogeneity in measures of the cortisol stress response has hampered a systematic evaluation of the evidence. We here report of a systematic literature review and meta-analysis on cortisol reactivity to psychosocial stress across psychiatric disorders. Original data from authors were obtained to construct standardized cortisol outcomes (the areas under the curve with respect to increase (AUCi) and ground (AUCg)) and to examine the influence of sex and symptomatic state on cortisol stress reactivity. Fourteen studies on major depressive disorder (MDD) (n = 1129), 9 on anxiety disorders (n = 732, including social anxiety disorder (SAD), posttraumatic stress disorder, panic disorder and mixed samples of anxiety disorders) and 4 on schizophrenia (n = 180) were included that used the Trier Social Stress Test or an equivalent psychosocial stress task. Sex-dependent changes in stress reactivity were apparent in MDD and anxiety disorders. Specifically, women with current MDD or an anxiety disorder exhibited a blunted cortisol stress response, whereas men with current MDD or SAD showed an increased cortisol response to psychosocial stress. In individuals with remitted MDD, altered cortisol stress reactivity was less pronounced in women and absent in men. For schizophrenia, cortisol stress reactivity was blunted in both men and women, but the number of studies was limited and showed evidence for publication bias. These findings illustrate that sharing individual data to disentangle the effects of sex, symptom levels and other factors is essential for further understanding of the alterations in cortisol stress reactivity across psychiatric disorders. [ABSTRACT FROM AUTHOR]

The GABA system is pivotal for an adequate response to a stressful environment but has remained largely unexplored in this context. The present study investigated the relationship of prospectively measured plasma GABA levels with psychopathology symptoms in military deployed to Afghanistan at risk for developing psychopathology following trauma exposure during deployment, including posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Plasma GABA levels were measured in military personnel (N = 731) one month prior to deployment (T0), and one (T1) and six months (T2) after deployment using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC–MS/MS). Mental health problems and depressive symptoms were measured with the Dutch revised Symptom Checklist (SCL-90) and PTSD symptoms with the Dutch Self-Rating Inventory for PTSD (SRIP). Six months after deployment increases in GABA concentrations were present in individuals who had developed mental health problems (T2: β = 0.06, p = 1.6 × 10 −2 , T1: β = 4.7 × 10 −2 , p = 0.13), depressive symptoms (T2: β = 0.29, p = 7.9 × 10 −3 , T1: β = 0.23, p = 0.072) and PTSD symptoms at T2 (T2: β = 0.12, p = 4.3 × 10 −2 , T1: β = 0.11, p = 0.13). Plasma GABA levels prior to and one month after deployment poorly predicted a high level of psychopathology symptoms either one or six months after deployment. The number of previous deployments, trauma experienced during deployment, childhood trauma, age and sex were not significantly associated with plasma GABA levels over time. Exclusion of subjects who either started or stopped smoking, alcohol or medication use between the three time points rendered the association of increasing GABA levels with the emergence of psychopathology symptoms more pronounced (mental health problems at T2: β = 0.09, p = 4.2 × 10 −3 ; depressive symptoms at T2: β = 0.35, p = 3.5 × 10 −3 , PTSD symptoms at T2: β = 0.17, p = 1.7 × 10 −2 ). To our knowledge, this is the first study to provide prospective evidence that the development of psychopathology after military deployment is associated with increasing plasma GABA levels. Our finding that plasma GABA rises after the emergence of psychopathology symptoms suggests that GABA increase may constitute a compensatory mechanism and warrants further exploration of the GABA system as a potential target for treatment. [ABSTRACT FROM AUTHOR]

Background Fear learning in stressful situations is highly adaptive for survival by steering behavior in subsequent situations, but fear learning can become disproportionate in vulnerable individuals. Despite the potential clinical significance, the mechanism by which stress modulates fear learning is poorly understood. Memory theories state that stress can cause a shift away from more controlled processing depending on the hippocampus toward more reflexive processing supported by the amygdala and striatum. This shift may be mediated by activation of the mineralocorticoid receptor (MR) for cortisol. We investigated how stress shifts processes underlying cognitively demanding learning versus less demanding fear learning using a combined trace and delay fear conditioning paradigm. Methods In a pharmacological functional magnetic resonance imaging study, we tested 101 healthy men probing the effects of stress (socially evaluated cold pressor vs. control procedure) and MR-availability (400 mg spironolactone vs. placebo) in a randomized, placebo-controlled, full-factorial, between-subjects design. Results Effective stress induction and successful conditioning were confirmed by subjective, physiologic, and somatic data. In line with a stress-induced shift, stress enhanced later recall of delay compared with trace conditioning in the MR-available groups as indexed by skin conductance responses. During learning, this was accompanied by a stress-induced reduction of learning-related hippocampal activity for trace conditioning. The stress-induced shift in fear and neural processing was absent in the MR-blocked groups. Conclusions Our results are in line with a stress-induced shift in fear learning, mediated by the MR, resulting in a dominance of cognitively less demanding amygdala-based learning, which might be particularly prominent in individuals with high MR sensitivity. [ABSTRACT FROM AUTHOR]

Glucocorticoids regulate memory consolidation, facilitating long-term storage of relevant information to adequately respond to future stressors in similar conditions. This effect of glucocorticoids is well-established and is observed in multiple types of behaviour that depend on various brain regions. By and large, higher glucocorticoid levels strengthen event-related memory, while inhibition of glucocorticoid signalling impairs consolidation. The mechanism underlying this glucocorticoid effect remains unclear, but it likely involves the transcriptional effects of the glucocorticoid receptor (GR). We here used a powerful paradigm to investigate the transcriptional effects of GR in the dorsal hippocampus of mice after training in an auditory fear conditioning task, aiming to identify a shortlist of GR target genes associated to memory consolidation. Therefore, we utilized in an explorative study the properties of selective GR modulators (CORT108297 and CORT118335), alongside the endogenous agonist corticosterone and the classical GR antagonist RU486, to pinpoint GR-dependent transcriptional changes. First, we confirmed that glucocorticoids can modulate memory strength via GR activation. Subsequently, by assessing the specific effects of the available GR-ligands on memory strength, we established a pharmacological filter which we imposed on the hippocampal transcriptome data. This identified a manageable shortlist of eight genes by which glucocorticoids may modulate memory consolidation, warranting in-depth follow-up. Overall, we showcase the strength of the concept of pharmacological transcriptome filtering, which can be readily applied to other research topics with an established role of glucocorticoids. • Glucocorticoid receptors modulate consolidation of auditory fear conditioning. • Selective glucocorticoid receptor modulators used to study glucocorticoid signalling. • Identification of a shortlist of genes associated to memory consolidation. • Glucocorticoids affect memory consolidation via both neuronal and non-neuronal cells. • Introducing the concept of a pharmacological transcriptome filter to study transcriptional effects. [ABSTRACT FROM AUTHOR]