Biomedical subjects

E Ronald de Kloet

Publications and source records attributed to E Ronald de Kloet.

At least 19 recordsLinked to original sources

PubMed2006

Adrenalectomy prevents behavioural sensitisation of mice to cocaine in a genotype-dependent manner.

The objective of the present study was to investigate the contribution of adrenal stress hormones to strain differences in cocaine sensitivity. For this purpose, we have studied sensitisation to the locomotor stimulant effect of cocaine and, in parallel, cocaine-induced corticosterone secretion in two inbred mouse strains: C57BL/6 and DBA/2. Adrenalectomy ('ADX': surgical removal of the adrenal glands) was performed in a subset of animals to investigate the contribution of the adrenals. ADX and SHAM operated mice were subjected to repeated injections of cocaine (15.0mg/kg) or saline for nine consecutive days, followed by a 5-day withdrawal interval and a saline challenge on day 14. All animals were challenged with 7.5mg/kg cocaine on day 15. We report that repeated cocaine exposure induced locomotor sensitisation in both strains, while endocrine sensitisation was only observed in the DBA/2 strain. By contrast, cocaine attenuated corticosterone responses in C57BL/6 mice throughout the sensitisation paradigm. We have therefore identified one strain, the DBA/2 strain, that displays parallel sensitisation of cocaine-induced locomotion and -corticosterone secretion. Most interestingly, ADX prevented locomotor sensitisation only in DBA/2 mice, suggesting that behavioural sensitisation depends on the integrity of adrenal function and on secretion of adrenal glucocorticoids in this strain. The present results demonstrate that adrenal stress hormones facilitate behavioural sensitisation to cocaine in a genotype-dependent manner and suggest that glucocorticoids contribute to strain differences in psychostimulant sensitivity.

Adrenalectomy↗

PubMed2006

A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness.

CONTEXT: Mineralocorticoid receptors (MR) mediate the action of aldosterone on sodium resorption in kidney tubular cells, but in brain they respond to the glucocorticoid cortisol in stress regulation and cognitive processes. OBJECTIVE: The objective of the study was to investigate the role of the MR gene variant I180V in the neuroendocrine response to a psychosocial stressor and in electrolyte regulation. DESIGN: Associations between the MRI180V and outcome variables in a healthy cohort subjected to psychosocial challenge (Trier Social Stress Test) and in a mild hypertensive cohort exposed to acute salt loading (Weinberger's test) were investigated. In vitro transactivational assays were applied to compare the effects of cortisol and aldosterone on the MRI180V. RESULTS: Carriers of the MR180V allele showed higher saliva (P < 0.01), plasma cortisol (P < 0.01), and heart rate responses (P < 0.05) to the Trier Social Stress Test than noncarriers (MR180I). After 3 d of a normal salt diet and the Weinberger's test, no association was found with urinary sodium excretion, plasma aldosterone, and plasma renin activity or with changes in blood pressure, aldosterone, and renin responses. In vitro testing of the MR180V allele revealed a mild loss of function using cortisol as a ligand, compared with the MR180I allele. Significantly higher doses of cortisol were needed for half-maximal induction on the TAT-1 (P < 0.002), TAT-3 (P < 0.03), or mouse mammary tumor virus (P < 0.02) promoters, whereas maximal induction was not different. These differences were not observed using aldosterone as a ligand. CONCLUSION: The findings reveal that cortisol and heart rate responses to a psychosocial stressor are enhanced in carriers of the MR180V variant.

Adaptation, Biological↗

PubMed2006

Hippocampal neuropathology of diabetes mellitus is relieved by estrogen treatment.

1. A recently recognized complication of uncontrolled diabetes mellitus is the encephalopathy involving, among other regions, the hippocampus. Since estrogens bring neuroprotection in cases of brain injury and degenerative diseases, we have studied if estradiol (E2) administration counteracts some hippocampal abnormalities of streptozotocin (STZ)-diabetic adult mice. 2. We first report the ability of E2 to modulate neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) of diabetic mice. Using bromodeoxyuridine (BrdU) to label newly generated cells, a strong reduction in cell proliferation was obtained in DG and SVZ of mice sacrificed 20 days after STZ administration. The reduction was completely relieved by 10 days of E2 pellet implantation, which increased 30-fold the circulating E2 levels. 3. Diabetic mice also showed abnormal expression of astrocyte markers in hippocampus. Thus, increased number of GFAP(+) cells, indicative of astrogliosis, and increased number of apolipoprotein-E (Apo-E)(+) astrocytes, a marker of ongoing neuronal dysfunction, was found in stratum radiatum below the CA1 hippocampal subfield of diabetic mice. Both parameters were reverted to normal by the E2 regime that upregulated cell proliferation. 4. The studies demonstrated that hippocampal neuropathology of uncontrolled diabetes is a reversible condition and sensitive to estrogen treatment. Studies in animal models may open up new venues for understanding the beneficial role of steroid hormones in diabetic encephalopathy.

Animals↗

PubMed2006

The effect of chronic exposure to highly aggressive mice on hippocampal gene expression of non-aggressive subordinates.

Exposure to a chronic psychosocial stressor changes the behavioral and neuroendocrine response pattern and causes structural changes in the rodent hippocampus. However, the underlying molecular mechanism of these changes induced by chronic stress is largely unknown. Recently, it was shown that exposure to a dominant highly aggressive mouse in the sensory contact model induced long-lasting stress symptoms in subordinate mice genetically selected for long attack latency (LAL mice). The aim of the present study was to study the effect of chronic stress on hippocampal gene expression in these subordinate LAL mice. GeneChips (Affymetrix) were used to compare gene expression profiles of LAL mice exposed to a sensory contact stressor for 25 days and their controls (one array per mouse, n=5 per line). After this stress paradigm, 131 genes were found differentially expressed (P<0.01). Strikingly, all of these genes showed a subtle downregulation in response to a chronic stressor. Interestingly, a significant overrepresentation of genes encoding structural components of ribosomes were found, suggesting diminished protein biosynthesis in the hippocampus of chronically stressed LAL mice. In addition, several genes of the NFkappaB signaling cascade, a pathway crucially involved in neuronal viability and neurite growth, were found to be downregulated. Together, we hypothesize that reduced NFkappaB signaling and diminished protein biosynthesis form part of the molecular mechanisms by which a chronic psychosocial stressor induces structural alterations in hippocampus of LAL mice.

Aggression↗

PubMed2006

From punch to profile.

In this essay an aspect of my research is highlighted that has its roots in the mid seventies with the implementation of the 'Palkovits punch' procedure. This methodology was introduced when radiochemical and radio-immunoassay methods became sufficiently sensitive to measure key molecules for chemical neurotransmission and metabolism in minute amounts of brain tissue. For application of today's laser guided microdissection this knowledge of functional neuro-anatomy is indispensable.

Brain↗

PubMed2005

Neuronal and astroglial alterations in the hippocampus of a mouse model for type 1 diabetes.

The influence of diabetes mellitus on brain pathology is increasingly recognized. Previous contributions of our laboratory demonstrated in models of type 1 diabetes (nonobese diabetic and streptozotocin (STZ)-treated mice), a marked astrogliosis and neurogenesis deficit in hippocampus and increased expression of hypothalamic neuropeptides. In the present investigation, we further analyzed alterations of astroglia and neurons in the hippocampus of mice 1 month after STZ-induced diabetes. Results showed that these STZ-diabetic mice presented: (a) increased number of astrocytes positive for apolipoprotein-E (Apo-E), a marker of ongoing neuronal dysfunction; (b) abnormal expression of early gene products associated with neuronal activation, including a high number of Jun + neurons in CA1 and CA3 layers and dentate gyrus, and of Fos-expressing neurons in CA3 layer; (c) augmented activity of NADPH-diaphorase, linked to oxidative stress, in CA3 region. These data support the concept that uncontrolled diabetes leads to hippocampal pathology, which adjoin to changes in other brain structures such as hypothalamus and cerebral cortex.

Animals↗

PubMed2005

The stress response to sensory contact in mice: genotype effect of the stimulus animal.

Male wild house mice selectively bred for long and short attack latency (LAL and SAL, respectively) were previously shown to respond differently to chronic sensory contact stress with another SAL male. In the present study, it was investigated whether the genotype of the opponent played a role in the differential stress response of LAL and SAL mice. To this end, a LAL or SAL male was housed either under standard conditions (i.e. with a female), single, or in sensory contact with another LAL or SAL male for a period of 5 days. This period was chosen in order to study stress response adaptations. Although social isolation (singly housed) already induced changes in some physiological markers, in particular in LAL mice, the highest number of stress-induced changes was observed in LAL and SAL males living opposite a male of the other genotype. This was indicated in LAL mice by higher corticosterone levels, adrenal hypertrophy, and reduced seminal vesicle weight, and in SAL mice by higher ACTH levels and adrenal hypertrophy. Some mechanisms through which LAL and SAL mice could perceive each other as being different are proposed in the discussion, but it remains unclear why these mice show a differential stress response depending on the genotype of the opponent. In conclusion, it was demonstrated that a psychosocial stressor triggered line-specific changes in LAL and SAL mice, which were shown to be determined by the genotype of the stressor. These results open a new avenue to investigate mechanisms underlying genotypic-dependent stress responses.

Adaptation, Psychological↗

PubMed2005

Corticosteroid receptor genetic polymorphisms and stress responsivity.

A fundamental question in the neuroendocrinology of stress-related psychopathology is why some individuals flourish and others perish under similar adverse conditions. In this contribution we focus on the variants of mineralocorticorticoid (MR) and glucocorticoid receptors (GR) that operate in balance and coordinate behavioral, autonomic, and neuroendocrine response patterns involved in homeostasis and health. In the GR-gene, three single nucleotide polymorphism (SNPs) have been associated with changes in metabolic profile and cardiovascular parameters: the ER22/23EK with a favorable and the N363S and the Bcl1 with a more adverse profile. Importantly, the N363S and the Bcl1 are found to increase cortisol responses to a psychosocial stressor. As a result, the whole body will suffer from overexposure with possible adverse effects on metabolism, cardiovascular control, immune function, and behavior. Also in the MR gene, variants are being identified that are associated with dysregulated autonomic, behavioral, and neuroendocrine responses. The data suggest that these MR and GR variants contribute to individual differences in resilience and vulnerability to stressors, and that these receptors therefore are potential drug targets for recovery of homeostasis and health.

Adaptation, Physiological↗

PubMed2004

Stress, genes and the mechanism of programming the brain for later life.

Adverse conditions during early life are a risk factor for stress-related diseases such as depression and post-traumatic stress disorder (PTSD). How this long-term effect of early adversity occurs is not known, although evidence accumulates that the action of stress hormones is an important determinant. In rodents after a variety of experiences, even minor ones, during postnatal life permanent changes in emotional and neuroendocrine reactivity have been observed. Also stressful events occurring prenatally and even the pre-implantation hormonal conditions can have permanent consequences. Here we will focus on evidence obtained from (i) the blastocyst implantation during conditions of ovarian hyperstimulation, which is commonly used in the generation of transgenic mice; (ii) the stress system activity in the newborn under various conditions of maternal care; (iii) the long-term consequences of maternal separation procedures. The results clearly demonstrate that early experiences trigger immediate changes in the stress system that may permanently alter brain and behaviour.

Animals↗

PubMed2004

Glucocorticoids and vulnerability to psychostimulant drugs: toward substrate and mechanism.

Glucocorticoid hormones can modulate the propensity of individuals to develop addictive behavior and, by doing so, contribute to the existence of individual differences in vulnerability to drugs. This article summarizes recent findings that increase our knowledge about drug-induced neuronal adaptations in the brain reward system and the role glucocorticoids may play in this process. Evidence exists that drugs and stress can induce similar changes in excitatory synaptic strength within the mesolimbic dopamine system, suggesting a coordinate mechanism for drugs of abuse and glucocorticoids. The glucocorticoid receptor (GR) plays an essential role in the stress-induced synaptic alterations, and studies using transgenic mice suggest that the GR is a key modulator of the motivation to take drugs and of the behavioral effects of repeated drug intake. The current state of research into the interplay between glucocorticoid hormones and addiction has reached a new phase in which detailed cellular and molecular analyses of the actual mechanisms will become possible. An important role is assigned to the GR, although many issues remain to be addressed, such as the actual site of glucocorticoid action in the brain, the molecular mechanisms and targets of GR-mediated glucocorticoid effects, and their interaction with genetic background.

Animals↗

PubMed2004

Basal and stress-induced differences in HPA axis, 5-HT responsiveness, and hippocampal cell proliferation in two mouse lines.

To characterize individual differences in neuroendocrine and neurochemical correlates of stress coping, two lines of wild house mice were studied. These mice are genetically selected for high and low aggression and show distinctly different behavioral strategies toward environmental stimuli. Long attack latency (LAL), low aggressive mice display a passive coping style, whereas short attack latency (SAL), high aggressive mice show an active coping style. It was hypothesized that this difference in behavioral coping style is associated with differences in stress system reactivity. This was tested by investigating the regulation of the hypothalamus-pituitary-adrenal (HPA) axis and the serotonin (5-HT) system and hippocampal cell proliferation rate in these mice under baseline and stress conditions. Baseline corticosterone output in LAL mice was found to be more sensitive to adrenocorticotropic hormone, but showed less day/night variation than in SAL mice. Furthermore, LAL mice showed lower hippocampal 5-HT(1A) receptor gene expression and function. Basal hippocampal cell proliferation rate was slightly lower in LAL than in SAL mice. Exposure to acute stress (forced swimming for 5 min) resulted in a hyper-reactive HPA response, a reduced increase in brain 5-HT metabolism, and an almost 50% reduction in hippocampal cell proliferation rate in LAL compared with SAL mice. Chronic psychosocial stress (sensory contact stress) induced long-lasting changes in the HPA axis in LAL, but not in SAL mice. In conclusion, these studies show that a genetic trait in behavioral coping style in wild house mice is associated with differences in HPA regulation, 5-HT neurotransmission, and hippocampal cell proliferation rate. The results further indicate that LAL mice have a higher stress responsivity than SAL mice. These results may have implications for a differential susceptibility for stress-related mood disorders.

Animals↗

PubMed2003

Differences in basal and stress-induced HPA regulation of wild house mice selected for high and low aggression.

Male wild house mice, selected for short (SAL) and long (LAL) attack latency, show distinctly different behavioral strategies in coping with environmental challenges. In this study, we tested the hypothesis that this difference in coping style is associated with a differential stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) system. SAL rather than LAL mice showed a clear fluctuation in circulating corticosterone concentrations around the circadian peak with significantly higher levels in the late light phase. LAL mice showed lower basal ACTH levels and higher thymic and spleen weights compared to SAL. Under basal conditions, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNA in the hippocampus and corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus were not different between the two lines. Forced swimming for 5 min induced high immobility behavior in LAL mice which was associated with an enhanced and prolonged corticosterone response as compared to SAL, while absolute ACTH levels did not differ. In addition, LAL mice showed an increase in hippocampal MR mRNA (but not GR) and hypothalamic CRH mRNA at 24 h after forced swimming. In conclusion, a genetic trait in coping style of wild house mice is associated with an idiosyncratic pattern of HPA activity, and greater responsiveness of physiological and molecular stress markers in LAL mice. In view of the profound differences in behavioral traits and stress system reactivity, these mouse lines genetically selected for attack latency present an interesting model for studying the mechanism underlying individual variation in susceptibility to stress-related psychopathology.

Acute Disease↗

PubMed2003

Large-scale gene expression profiling of discrete brain regions: potential, limitations, and application in genetics of aggressive behavior.

Many behavioral geneticists are interested in unraveling the molecular mechanisms underlying aggressive behavior. So far, most scientists have based their search for aggression-related genes on a preliminary functional hypothesis. Large-scale gene expression profiling techniques, such as serial analysis of gene expression (SAGE) and DNA microarrays, now enable the screening of expression levels of thousands of genes simultaneously, allowing the identification of new candidate aggression-related genes expressed in brain and thus the generation of new hypotheses. However, expression profiling in the brain is challenging, as brain is a complex heterogeneous tissue where large numbers of genes are expressed and relatively small changes in gene expression occur. In this special issue, we focus on the principles of SAGE and DNA microarrays, as well as their advantages and disadvantages and application to analysis in brain tissue in order to identify aggression-related genes.

Aggression↗

PubMed2003

Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse.

The aim of the study is to test whether fluvoxamine affects the function of the hypothalamic pituitary adrenal (HPA) axis in female borderline (borderline personality disorder, BPD) patients with and without a history of sustained childhood abuse. Special attention is given to the presence of comorbid major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The HPA axis of 30 female BPD patients with (n = 17) and without (n = 13) a history of sustained childhood abuse was challenged with a combined dexamethasone and corticotropin releasing hormone test (DEX/CRH test) before and after 6 (n = 14) and 12 (n = 16) weeks of fluvoxamine treatment (150 mg/day). Both 6- and 12-week fluvoxamine treatments were associated with a significant and robust reduction of the adrenocorticotrophic hormone (ACTH) and cortisol response to the DEX/CRH test. The magnitude of the reduction was dependent on the presence of sustained childhood abuse, but not on the presence of comorbid MDD or PTSD: patients with a history of sustained childhood abuse showed the strongest reduction in ACTH and cortisol. In conclusion, Fluvoxamine treatment reduces the hyperresponsiveness of the HPA axis in BPD patients with a history of sustained childhood abuse. This effect is likely to be obtained in the first 6 weeks of treatment.

Adult↗

PubMed2003

Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice.

The genetically selected long attack latency (LAL) and short attack latency (SAL) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus-pituitary-adrenocortical (HPA)-axis. Serial analysis of gene expression (SAGE) was used to generate a hippocampal expression profile of almost 30 000 genes in LAL and SAL mice. Using SAGE, we found differential expression of 191 genes. Among these were genes involved in growth, signal transduction, and cell metabolism. The SAGE study was supported by GeneChip analysis (Affymetrix). Strikingly, both SAGE and GeneChips showed a higher expression of numerous cytoskeleton genes, such as cofilin and several tubulin isotypes in LAL mice. LAL mice also showed a higher expression of several calmodulin-related genes and genes encoding components of a MAPK cascade, namely raf-related oncogene and ERK2. The findings were confirmed by in situ hybridization. Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf/ERK pathway that may be related to structural differences in the hippocampus of LAL and SAL mice. As stress-related disorders, such as depression, are also linked to differential regulation of the HPA-axis and the serotonergic system and are associated with altered hippocampal morphology, differential regulation of these genes may be involved in the pathogenesis of these diseases.

Aggression↗

PubMed2003

Hormones, brain and stress.

The stress system orchestrates body and brain responses to the environment. This action exerted by the mediators of the stress system has two modes of operation. The immediate response mode driven by corticotropin-releasing hormone (CRH) organises via CRH-1 receptors the behavioural, sympathetic and hypothalamic-pituitary-adrenal (HPA) responses to a stressor. In the other - slower - mode, which facilitates behavioural adaptation, the urocortins acting through CRH-2 receptors seem prominent. Corticosteroid hormones secreted by the adrenal cortex are implicated in both modes through their high affinity type 1 (mineralocorticoid receptors - MR) and lower affinity type 2 (glucocorticoid receptors - GR) receptors that are co-localised in limbic neural circuitry. Current data suggest that MR controls in specific afferents the threshold or sensitivity of the fast CRH-1 driven stress system mode and thus prevents disturbance of homeostasis, while GR facilitates its recovery by restraining in these very same circuits stress responses and by mobilising energy resources. In preparation for future events GR facilitates behavioural adaptation and promotes storage of energy. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance and health. Imbalance induced by genetic modification or chronic stressors changes specific neural signalling pathways underlying psychic domains of cognition and emotion, anxiety and aggression. This Yin-Yang stress concept is fundamental for genomic strategies to understand the mechanistic underpinning of cortisol-induced stress-related disorders such as i.e. severe forms of depression and co-morbid diseases.

Animals↗

PubMed2002

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse.

BACKGROUND: High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS: We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS: Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS: Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.

Adolescent↗

PubMed2002

The HPA system during the postnatal development of CD1 mice and the effects of maternal deprivation.

In this study we describe in 9- and 18-day-old CD1 mice (i) the basal and stress-induced activity of markers of the HPA system in blood, brain and pituitary, (ii) the effects of a 24-h maternal deprivation and (iii) the influence of anogenital stimulation (stroking) in deprived pups on these markers. We found low basal concentrations of ACTH and corticosterone at postnatal day (pnd) 9 and no or little response to a mild stressor at this age, confirming the existence of a SHRP in mice. At pnd 18 the mice displayed an adult-like ACTH and corticosterone response following a mild stressor. Maternal deprivation resulted in enhanced basal and stress levels of corticosterone at both ages. Interestingly, basal ACTH levels were elevated following maternal deprivation at pnd 9. At pnd 18 maternal deprivation resulted in a blunted ACTH response. Maternal deprivation resulted in a down-regulation of GR, MR, CRH and POMC transcript in the brain. However, maternally deprived 18-day-old pups displayed increased levels of CRH and POMC transcript, while GR and MR mRNA was also down-regulated. Anogenital stroking could reverse maternal deprivation effects on ACTH and MR mRNA, but not CRH mRNA. We conclude that (i) at the two measured time points the HPA axis develops similar in mice as in rats, (ii) maternal deprivation has pronounced effects in mice, which are similar to that found in the rat and (iii) there are a number of significant differences, which mainly concern the central CRH-ACTH components of the axis.

Adrenocorticotropic Hormone↗