Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition.

Converging evidence suggests that females and males show different responses to stress; however, little is known about the mechanism underlying the sexually dimorphic effects of stress. In this study, we found that young female rats exposed to 1 week of repeated restraint stress show no negative effects on temporal order recognition memory (TORM), a cognitive process controlled by the prefrontal cortex (PFC), which was contrary to the impairment in TORM observed in stressed males. Concomitantly, normal glutamatergic transmission and glutamate receptor surface expression in PFC pyramidal neurons were found in repeatedly stressed females, in contrast to the significant reduction seen in stressed males. The detrimental effects of repeated stress on TORM and glutamate receptors were unmasked in stressed females when estrogen receptors were inhibited or knocked down in PFC, and were prevented in stressed males with the administration of estradiol. Blocking aromatase, the enzyme for the biosynthesis of estrogen, revealed the stress-induced glutamatergic deficits and memory impairment in females, and the level of aromatase was significantly higher in the PFC of females than in males. These results suggest that estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and PFC-dependent cognition, which may underlie the stress resilience of females.

Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory.

Corticosteroid stress hormones have a strong impact on the function of prefrontal cortex (PFC), a central region controlling cognition and emotion, though the underlying mechanisms are elusive. We found that behavioral stressor or short-term corticosterone treatment in vitro induces a delayed and sustained potentiation of the synaptic response and surface expression of N-methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in PFC pyramidal neurons through a mechanism depending on the induction of serum- and glucocorticoid-inducible kinase (SGK) and the activation of Rab4, which mediates receptor recycling between early endosomes and the plasma membrane. Working memory, a key function relying on glutamatergic transmission in PFC, is enhanced in acutely stressed animals through an SGK-dependent mechanism. These results suggest that acute stress, by activating glucocorticoid receptors, increases the trafficking and function of NMDARs and AMPARs through SGK/Rab4 signaling, which leads to the potentiated synaptic transmission, thereby facilitating cognitive processes mediated by the PFC.

Chronic stress, metabolism, and metabolic syndrome.

The prevalence of obesity has rapidly escalated and now represents a major public health concern. Although genetic associations with obesity and related metabolic disorders such as diabetes and cardiovascular disease have been identified, together they account for a small proportion of the incidence of disease. Environmental influences such as chronic stress, behavioral and metabolic disturbances, dietary deficiency, and infection have now emerged as contributors to the development of metabolic disease. Although epidemiological data suggest strong associations between chronic stress exposure and metabolic disease, the etiological mechanisms responsible remain unclear. Mechanistic studies of the influence of chronic social stress are now being conducted in both rodent and nonhuman primate models, and phenotypic results are consistent with those in humans. The advantage of these models is that potential neural mechanisms may be examined and interventions to treat or prevent disease may be developed and tested. Further, circadian disruption and metabolic conditions such as diabetes mellitus could increase susceptibility to other stressors or serve as a stressor itself. Here, we review data from leading investigators discussing the interrelationship between chronic stress and development of metabolic disorders.

Stress and glucocorticoid modulation of feeding and metabolism.

This perspective highlights research presented as part of the symposium entitled, "Stress and Glucocorticoid Modulation of Feeding and Metabolism" at the 2018 Neurobiology of Stress Workshop held in Banff, AB, Canada. The symposium comprised five researchers at different career stages who each study different aspects of the interaction between the stress response and metabolic control. Their collective results reveal the complexity of this relationship in terms of behavioural and physiological outcomes. Their work emphasizes the need to consider the level of interaction (cellular, tissue, systems) as well as the timing and context in which the interaction is studied. Rather than a comprehensive review on the work presented at the Symposium, here we discuss recurring themes that emerged at the biennial workshop, which address new avenues of research that will drive the field forward.

The Complexity of Simplicity: Role of Sex, Development and Environment in the Modulation of the Stress Response.

Anecdotally, we all know that stress is 'complicated', although most stress research is undertaken using incredibly simplified models that may not allow us to fully understand the underlying interactive mechanisms present in the 'real world'. This attempt at simplification, although sometimes necessary, may explain some of the difficulties faced when integrating basic science findings with the clinical and epidemiological data on stress and stress-related disorders. In a symposium held at the 2015 International Society for Psychoneuroendocrinology meeting in Edinburgh, UK, a series of speakers explored 'The Many Pathways to Plasticity in the Stress System', specifically focusing on variables that, in many cases, are eliminated from studies of stress to provide increased experimental control. Specifically, four speakers tackled the complex contributions of 'Sex, Development and Environment' in stress research, and reported published and unpublished evidence from work conducted in their own laboratories demonstrating that, in our race for simplicity in experimentation, the stories that we tell become all the more complex.

Somatic and Neuroendocrine Changes in Response to Chronic Corticosterone Exposure During Adolescence in Male and Female Rats.

Prolonged stress and repeated activation of the hypothalamic-pituitary-adrenal axis can result in many sex-dependent behavioural and metabolic changes in rats, including alterations in feeding behaviour and reduced body weight. In adults, these effects of stress can be mimicked by corticosterone, a major output of the hypothalamic-pituitary-adrenal axis, and recapitulate the stress-induced sex difference, such that corticosterone-treated males show greater weight loss than females. Similar to adults, chronic stress during adolescence leads to reduced weight gain, particularly in males. However, it is currently unknown whether corticosterone mediates this somatic change and whether additional measures of neuroendocrine function are affected by chronic corticosterone exposure during adolescence in a sex-dependent manner. Therefore, we examined the effects of non-invasively administered corticosterone (150 or 300 µg/ml) in the drinking water of male and female rats throughout adolescent development (30-58 days of age). We found that adolescent animals exposed to chronic corticosterone gain significantly less weight than controls, which may be partly mediated by the effects of corticosterone on food consumption, fluid intake and gonadal hormone function. Our data further show that, despite similar circulating corticosterone levels, males demonstrate a greater sensitivity to these changes than females. We also found that Npy1 and Npy5 receptor mRNA expression, genes implicated in appetite regulation, was significantly reduced in the ventral medial hypothalamus of corticosterone-treated males and females compared to controls. Finally, parameters of gonadal function, such as plasma sex steroid concentrations and weight of reproductive tissues, were reduced by adolescent corticosterone treatment, although only in males. The data obtained in the present study indicate that chronic corticosterone exposure throughout adolescent development results in significant and sex-dependent somatic and neuroendocrine changes, and the results also provide an experimental framework for further investigating the impact of corticosterone on metabolic and neuroendocrine function during adolescence.

Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice.

Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 µg/ml) and measured cannabinoid CB(1) receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB(1) receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB(1) receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB(1) receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB(1) receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB(1) receptor density and augment AEA metabolism within limbic structures.