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Posttraumatic stress disorder (PTSD) is characterized by a hypermnesia of the trauma and by a memory impairment that decreases the ability to restrict fear to the appropriate context. Infusion of glucocorticoids in the hippocampus after fear conditioning induces PTSD-like memory impairments and an altered pattern of neural activation in the hippocampal-amygdalar circuit. Mice become unable to identify the context as the correct predictor of the threat and show fear responses to a discrete cue not predicting the threat in normal conditions. These data demonstrate PTSD-like memory impairments in rodents and identify a potential pathophysiological mechanism of this condition.

[This corrects the article DOI: 10.1155/2013/405127.].

In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.

In the published manuscript [...]

Bisphenol A (BPA) is classified as an endocrine disruptor that mainly mimics the effects of estrogen and disrupts the synthesis of male androgens. Due to the toxicity of BPA, some new analogs, such as bisphenol BPB, BPC, BPF, PBH, and BPZ, were introduced into the market. The goal of this research was to demonstrate the applicability of kinetic analysis, in particular, Lineweaver-Burk plots, in assessing the impact of bisphenol Z on enzymatic activity. This study aimed to characterize the inhibitory effects of BPZ on 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity in the transformation of 11-dehydrocorticosterone (DHC) to corticosterone (CORT). During the determination of the enzymatic reaction product, chromatographic analysis conditions were optimized using gradient elution and an Acquity UPLC BEH C18 chromatographic column. The retention time of the assayed corticosterone was approximately 2 min. Also described and compared were graphical methods of analysis and data interpretation, such as Lineweaver-Burk, Eadie-Hofstee, and Hanes-Woolf plots. The experiments demonstrated that bisphenol Z is a mixed 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor, responsible for catalyzing the conversion of 11-dehydrocorticosterone (DHC) to corticosterone (CORT). This relationship was confirmed by analyzing Lineweaver-Burk plots, which showed an increase in apparent KM with a decrease in the constant Vmax, suggesting a mixed inhibition mechanism. Molecular docking and detailed analysis of the interaction profiles revealed that BPZ consistently occupies the active site cavities of all examined enzymes (rat and human 11β-HSD1 and Arabidopsis 11β-HSD2), forming a stabilizing network of non-covalent interactions. Our research has significant biological significance considering the role of the 11β-HSD1 enzyme in the conversion of DHC to CORT and the importance of this process and its functions in adipose tissue, the liver, and the brain.

Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.

Glucocorticoids are a family of hormones that coordinate diverse physiological processes in responding to stress. Prolonged glucocorticoid exposure over weeks has been linked to dendritic atrophy and spine loss in fixed tissue studies of adult brains, but it is unclear how glucocorticoids may affect the dynamic processes of dendritic spine formation and elimination in vivo. Furthermore, relatively few studies have examined the effects of stress and glucocorticoids on spines during the postnatal and adolescent period, which is characterized by rapid synaptogenesis followed by protracted synaptic pruning. To determine whether and to what extent glucocorticoids regulate dendritic spine development and plasticity, we used transcranial two-photon microscopy to track the formation and elimination of dendritic spines in vivo after treatment with glucocorticoids in developing and adult mice. Corticosterone, the principal murine glucocorticoid, had potent dose-dependent effects on dendritic spine dynamics, increasing spine turnover within several hours in the developing barrel cortex. The adult barrel cortex exhibited diminished baseline spine turnover rates, but these rates were also enhanced by corticosterone. Similar changes occurred in multiple cortical areas, suggesting a generalized effect. However, reducing endogenous glucocorticoid activity by dexamethasone suppression or corticosteroid receptor antagonists caused a substantial reduction in spine turnover rates, and the former was reversed by corticosterone replacement. Notably, we found that chronic glucocorticoid excess led to an abnormal loss of stable spines that were established early in life. Together, these findings establish a critical role for glucocorticoids in the development and maintenance of dendritic spines in the living cortex.

Synopsis Reference to glucocorticoids as “stress hormones” has been growing in prevalence in the literature, including in comparative and environmental endocrinology. Although glucocorticoids are elevated in response to a variety of stressors in vertebrate animals, the primary functions of glucocorticoids are not responding to stressors and they are only one component of complex suite of physiological and behavioral responses to stressors. Thus, the use of the short-hand phrase “stress hormone” can be misleading. Further, simply measuring glucocorticoids is not equivalent to measuring a stress response, nor is manipulating glucocorticoids equivalent to exposing an animal to a stressor. In this commentary we highlight the problems with using functional names for hormones, and of treating cortisol or corticosterone as synonymous with stress. We provide recommendations to add clarity to the presentation of research on this topic, and to avoid conflation of glucocorticoids with stressors and the stress response in the design of experiments.

Immune responses have been mostly studied at a specific time in anuran species. However, time-changes related to immunomodulation associated with glucocorticoid (GC) alterations following stressors and GC treatment are complex. The present study describes time-related changes in immune response and corticosterone (CORT) plasma levels following restraint challenge, short, mid and long-term captivity, and CORT exogenous administration by transdermal application (TA) in Rhinella ornata toads. We observed increased neutrophil: lymphocyte ratios after restraint challenge and CORT TA, without changes following short and mid-term captivity. Plasma bacterial killing ability was sustained in all treatments, except long-term captivity, with decreased values after 90 days under such conditions. Phagocytic activity of peritoneal cells increased after mid-term captivity, and the phytohemagglutinin swelling response was impaired in those animals treated with CORT TA for 20 consecutive days. Plasma CORT levels increased or were sustained after restraint challenge (depending on initial values), decreased following mid and long-term captivity (for those animals showing high CORT in the field) and increased after 20 days of CORT TA. By performing assessments of time-changes in immune processes and CORT plasma levels in R. ornata, we demonstrate immuno-enhancing effects following restraint, short and mid-term stressors, while long-term stressors and CORT TA promoted immunosuppression in these toads.

Infant maltreatment increases vulnerability to physical and mental disorders, yet specific mechanisms embedded within this complex infant experience that induce this vulnerability remain elusive. To define critical features of maltreatment-induced vulnerability, rat pups were reared from postnatal day 8 (PN8) with a maltreating mother, which produced amygdala and hippocampal deficits and decreased social behavior at PN13. Next, we deconstructed the maltreatment experience to reveal sufficient and necessary conditions to induce this phenotype. Social behavior and amygdala deficits (volume, neurogenesis, c-Fos, local field potential) required combined chronic high corticosterone and maternal presence (not maternal behavior). Hippocampal deficits were induced by chronic high corticosterone regardless of social context. Causation was shown by blocking corticosterone during maltreatment and suppressing amygdala activity during social behavior testing. These results highlight (1) that early life maltreatment initiates multiple pathways to pathology, each with distinct causal mechanisms and outcomes, and (2) the importance of social presence on brain development.