The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies... Show moreThe two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages. Show less
Corticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as... Show moreCorticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as transcription factors. Corticosteroid effects can be highly divergent, depending on the receptor type, but also on brain region, cell type, and physiological context. These differences ultimately depend on differential interactions of MR and GR with other proteins, which determine ligand binding, nuclear translocation, and transcriptional activities. In this review, we discuss established and potential mechanisms that confer receptor and cell type-specific effects of the MR and GR-mediated transcriptional effects in the brain. Show less
Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant... Show morePsychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates the blood-brain barrier, but seems to facilitate the entry of cortisol. We also report that in male C57BL/6J mice, after a 7-day treatment with a high dose of mifepristone, basal blood corticosterone levels were similar to that of vehicle controls. This is surprising because after the first mifepristone challenge, corticosterone remained elevated for about 16 h, and then decreased towards vehicle control levels at 24 h. At that time, stress-induced corticosterone levels of the 1xMIF were sevenfold higher than the 7xMIF group, the latter response being twofold lower than controls. The 1xMIF mice showed behavioral hyperactivity during exploration of the circular hole board, while the 7xMIF mice rather engaged in serial search patterns. To explain this rapid reset of corticosterone secretion upon recurrent mifepristone administration, we suggest the following: (i) A rebound glucocorticoid feedback after cessation of mifepristone treatment. (ii) Glucocorticoid agonism in transrepression and recruitment of cell-specific coregulator cocktails. (iii) A more prominent role of brain MR function in control of stress circuit activity. An overview table of neuroendocrine MIF effects is provided. The data are of interest for understanding the mechanistic underpinning of stress system reset as treatment strategy for stress-related diseases. Show less
Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there... Show moreDexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development. (C) 2012 Elsevier B.V. All rights reserved. Show less
Horst, J. ter; Kloet, E.R. de; Schachinger, H.; Oitzl, M.S. 2012
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... Show moreThere 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. Show less
Groeneweg, F.L.; Karst, H.; Kloet, E.R. de; Joels, M. 2012
The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both... Show moreThe balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor alpha. (C) 2011 Elsevier Ireland Ltd. All rights reserved. Show less
Claessens, S.E.F.; Daskalakis, N.P.; Veen, R. van der; Oitzl, M.S.; Kloet, E.R. de; Champagne, D.L. 2011
Human epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life.... Show moreHuman epidemiology and animal studies have convincingly shown the long-lasting impact of early life experiences on the development of individual differences in stress responsiveness in later life. The interplay between genes and environment underlies this phenomenon.We provide an overview of studies investigating the impact of early life experiences on the development of individual differences in neuroendocrine stress responsiveness in adulthood and address (1) impact of environment on later stress phenotypes, (2) role of genetic factors in modulating the outcome of environment, and (3) role of nonshared environmental experience in the outcome of gene x environment interplays. We present original findings where we investigated the influence of nonshared experiences in terms of individual differences in maternal care received, on the development of stress phenotype in later life in rats.Environmental influences in early life exert powerful effects on later stress phenotypes, but they do not always lead to expression of diseases. Heterogeneity in response is explained by the role of particular genetic factors in modulating the influence of environment. Nonshared experiences are important in the outcome of gene x environment interplays in humans. We show that nonshared experiences acquired through within-litter variation in maternal care in rats predict the stress phenotype of the offspring.The outcome of early experience is not deterministic and depends on several environmental and genetic factors interacting in an intricate manner to support stress adaptation. The degree of "match" and "mismatch" between early and later life environments predicts resilience and vulnerability to stress-related diseases, respectively. Show less
