Corticosterone Alters AMPAR Mobility and Facilitates Bidirectional Synaptic Plasticity

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

Association of childhood trauma with cognitive function in healthy adults: a pilot study

BACKGROUND: Animal and human studies suggest that stress experienced early in life has detrimental consequences on brain development, including brain regions involved in cognitive function. Cognitive changes are cardinal features of depression and posttraumatic stress disorder. Early-life trauma is a major risk factor for these disorders. Only few studies have measured the long-term consequences of childhood trauma on cognitive function in healthy adults. METHODS: In this pilot study, we investigated the relationship between childhood trauma exposure and cognitive function in 47 healthy adults, who were identified as part of a larger study from the general population in Wichita, KS. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Wide-Range-Achievement-Test (WRAT-3) to examine cognitive function and individual achievement. Type and severity of childhood trauma was assessed by the Childhood Trauma Questionnaire (CTQ). Data were analyzed using multiple linear regression on CANTAB measures with primary predictors (CTQ scales) and potential confounders (age, sex, education, income). RESULTS: Specific CTQ scales were significantly associated with measures of cognitive function. Emotional abuse was associated with impaired spatial working memory performance. Physical neglect correlated with impaired spatial working memory and pattern recognition memory. Sexual abuse and physical neglect were negatively associated with WRAT-3 scores. However, the association did not reach the significance level of p < 0.01. CONCLUSIONS: Our results suggest that physical neglect and emotional abuse might be associated with memory deficits in adulthood, which in turn might pose a risk factor for the development of psychopathology

Stress Hormones Receptors in the Amygdala Mediate the Effects of Stress on the Consolidation, but Not the Retrieval, of a Non Aversive Spatial Task

This study examined the effects of the arousal level of the rat and exposure to a behavioral stressor on acquisition, consolidation and retrieval of a non-aversive hippocampal-dependent learning paradigm, the object location task. Learning was tested under two arousal conditions: no previous habituation to the experimental context (high novelty stress/arousal level) or extensive prior habituation (reduced novelty stress/arousal level). Results indicated that in the habituated rats, exposure to an out-of-context stressor (i.e, elevated platform stress) impaired consolidation and retrieval, but not acquisition, of the task. Non-habituated animals under both stressed and control conditions did not show retention of the task. In habituated rats, RU-486 (10 ng/side), a glucocorticoid receptor (GR) antagonist, or propranolol (0.75 µg/side), a beta-adrenergic antagonist, injected into the basolateral amygdala (BLA), prevented the impairing effects of the stressor on consolidation, but not on retrieval. The CB1/CB2 receptor agonist WIN55,212-2 (WIN, 5 µg/side) microinjected into the BLA did not prevent the effects of stress on either consolidation or retrieval. Taken together the results suggest that: (i) GR and β-adrenergic receptors in the BLA mediate the impairing effects of stress on the consolidation, but not the retrieval, of a neutral, non-aversive hippocampal-dependent task, (ii) the impairing effects of stress on hippocampal consolidation and retrieval are mediated by different neural mechanisms (i.e., different neurotransmitters or different brain areas), and (iii) the effects of stress on memory depend on the interaction between several main factors such as the stage of memory processing under investigation, the animal's level of arousal and the nature of the task (neutral or aversive)

The Cortisol Response to Anticipated Intergroup Interactions Predicts Self-Reported Prejudice

Objectives: While prejudice has often been shown to be rooted in experiences of threat, the biological underpinnings of this threat–prejudice association have received less research attention. The present experiment aims to test whether activations of the hypothalamus-pituitary-adrenal (HPA) axis, due to anticipated interactions with out-group members, predict self-reported prejudice. Moreover, we explore potential moderators of this relationship (i.e., interpersonal similarity; subtle vs. blatant prejudice). Methodology/Principal findings: Participants anticipated an interaction with an out-group member who was similar or dissimilar to the self. To index HPA activation, cortisol responses to this event were measured. Then, subtle and blatant prejudices were measured via questionnaires. Findings indicated that only when people anticipated an interaction with an out-group member who was dissimilar to the self, their cortisol response to this event significantly predicted subtle (r =.50) and blatant (r =.53) prejudice. Conclusions: These findings indicate that prejudicial attitudes are linked to HPA-axis activity. Furthermore, when intergroup interactions are interpreted to be about individuals (and not so much about groups), experienced threat (or its biological substrate) is less likely to relate to prejudice. This conclusion is discussed in terms of recent insights from social neuroscience

Blocking Mineralocorticoid Receptors prior to Retrieval Reduces Contextual Fear Memory in Mice

BACKGROUND: Corticosteroid hormones regulate appraisal and consolidation of information via mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respectively. How activation of these receptors modulates retrieval of fearful information and the subsequent expression of fear is largely unknown. We tested here whether blockade of MRs or GRs during retrieval also affects subsequent expression of fear memory. METHODOLOGY/PRINCIPAL FINDINGS: Mice were trained in contextual or tone cue fear conditioning paradigms, by pairing mild foot shocks with a particular context or tone respectively. Twenty-four hours after training, context-conditioned animals were re-exposed to the context for 3 or 30 minutes (day 2); tone-conditioned animals were placed in a different context and re-exposed to one or six tones. Twenty-four hours (day 3) and one month later, freezing behavior to the aversive context/tone was scored again. MR or GR blockade was achieved by giving spironolactone or RU486 subcutaneously one hour before retrieval on day 2. Spironolactone administered prior to brief context re-exposure reduced freezing behavior during retrieval and 24 hours later, but not one month later. Administration of spironolactone without retrieval of the context or immediately after retrieval on day 2 did not reduce freezing on day 3. Re-exposure to the context for 30 minutes on day 2 significantly reduced freezing on day 3 and one month later, but freezing was not further reduced by spironolactone. Administration of spironolactone prior to tone-cue re-exposure on day 2 did not affect freezing behavior. Treatment with RU486 prior to re-exposure did not affect context or tone-cue fear memories at any time point. CONCLUSIONS/SIGNIFICANCE: We conclude that MR blockade prior to retrieval strongly reduces the expression of contextual fear, implying that MRs, rather than GRs, play an important role in retrieval of emotional information and subsequent fear expression

Relevance of Stress and Female Sex Hormones for Emotion and Cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders

The enhancement of stress-related memory by glucocorticoids depends on synapsin-Ia/Ib

The activation of glucocorticoid receptors (GR) by glucocorticoids increases stress-related memory through the activation of the MAPK signaling pathway and the downstream transcription factor Egr-1. Here, using converging in vitro and in vivo approaches, respectively, GR-expressing cell lines, culture of hippocampal neurons, and GR genetically modified mice (GRNesCre), we identified synapsin-Ia/Ib as one of the effectors of the glucocorticoid signaling cascade. Stress and glucocorticoid-induced activation of the GR modulate synapsin-Ia/Ib through two complementary mechanisms. First, glucocorticoids driving Egr-1 expression increase the expression of synapsin-Ia/Ib, and second, glucocorticoids driving MAPK activation increase its phosphorylation. Finally, we showed that blocking fucosylation of synapsin-Ia/Ib in the hippocampus inhibits its expression and prevents the glucocorticoid-mediated increase in stress-related memory. In conclusion, our data provide a complete molecular pathway (GR/Egr-1/MAPK/Syn-Ia/Ib) through which stress and glucocorticoids enhance the memory of stress-related events and highlight the function of synapsin-Ia/Ib as molecular effector of the behavioral effects of stress

Early maternal deprivation affects dentate gyrus structure and emotional learning in adult female rats

Rationale: Stress elicits functional and structural changes in the hippocampus. Early life stress is one of the major risk factors for stress-related pathologies like depression. Patients suffering from depression show a reduced hippocampal volume, and in women, this occurs more often when depression is preceded by childhood trauma. However, the underlying mechanisms that account for a reduced hippocampal volume are unknown. Objective: We examined the effects of maternal absence on structure and function of the hippocampus in female offspring. Methods: We studied whether 24 h of maternal deprivation (MD) on postnatal day 3 altered adult neurogenesis, individual neuronal morphology and dentate gyrus (DG) structure in young adult female rats. In addition, functional alterations were addressed by studying synaptic plasticity in vitro, and spatial as well as emotional learning was tested. Results: Adult females that were subjected to MD revealed significant reductions in DG granule cell number and density. In addition, DG neurons were altered in their dendritic arrangement. No effects on the rate of adult neurogenesis were found. Furthermore, MD did not alter synaptic plasticity in vitro, neither under normal nor high-stress conditions. In addition, spatial learning and contextual fear conditioning were comparable between control and MD animals. However, MD animals showed an improved amygdala-dependent fear memory. Conclusion: Although early life stress exposure did not impair hippocampus-dependent functioning in female offspring, it irreversibly affected DG structure by reducing cell numbers. This may be relevant for the reduced hippocampal volume observed in depression and the increased vulnerability of women to develop depression