Stress Hormone System Research Articles

Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions

Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

Pharmacological interference with the glucocorticoid system influences symptoms and lifespan in a mouse model of Rett syndrome

Rett syndrome (RTT) is caused by loss-of-function mutations in the X-linked gene MECP2 coding for methyl CpG-binding protein 2 (MeCP2). This protein can act as transcriptional repressor, and we showed in a previous study that glucocorticoid-inducible genes are up-regulated in an RTT mouse model and that these genes are direct MeCP2 targets. Here, we report that pharmacological intervention with the glucocorticoid system has an impact on the symptoms and lifespan in an RTT mouse model. Our data support a functional implication of the stress hormone system in RTT and suggest this hormone system as potential therapeutic target.

Abuse History, Depression, and Somatization Are Associated With Gastric Sensitivity and Gastric Emptying in Functional Dyspepsia

Gastric sensitivity testing relies on subjective reporting and may therefore be influenced by psychosocial factors and somatization. Furthermore, psychological processes may affect gastric motor function (accommodation to a meal emptying) through efferent brain-gut pathways. This study sought to determine the association of abuse history, psychiatric comorbidity, and somatization with gastric sensorimotor function. In 201 patients with functional dyspepsia, gastric sensitivity and accommodation were studied with a barostat. Gastric emptying of solids was studied using a breath test. Sexual and physical abuse history, psychiatric comorbidity (depression and panic disorder), and somatization were assessed using validated questionnaires. Multiple linear regression models were used to identify patient characteristics independently associated with gastric sensitivity and emptying. Age (p = .02), sexual abuse history (p < .001), physical abuse history (p = .004), and somatization (p < .001) were independently associated with gastric discomfort threshold (R(2) = 0.30); a significant depression-by-sexual abuse interaction effect was also found (p = .003). None of the factors studied were associated with gastric accommodation to a meal. Physical abuse history (p = .003) and somatization (p = .048) were independently associated with gastric emptying (R(2) = 0.19). These results demonstrate the complex relationship among abuse history, psychiatric comorbidity, somatization, and gastric sensorimotor (dys)function. Although the psychobiological mechanisms underlying these relationships remain to be determined, the autonomic nervous, stress hormone, and immune systems may be involved.

Interaction of FKBP5 Gene Variants and Adverse Life Events in Predicting Depression Onset: Results From a 10-Year Prospective Community Study

The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress hormone system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode. The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14-24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping. While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study. These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.

Glucocorticoids as Predictors of Treatment Response in Depression

Glucocorticoids and the stress hormone system have been implicated in the pathophysiology of depression and in the mechanism of action of antidepressant response. Many studies have investigated this system in an effort to predict response to antidepressant treatment. The purpose of this review is to evaluate the evidence for using glucocorticoid-related measures for personalized treatment of depression. We conducted a MEDLINE search from 1966 through 2010 and examined English-language studies reporting on the use of endocrine challenge tests and genetic polymorphisms in genes regulating the stress hormone system as predictors of antidepressant response. While measures of glucocorticoid levels using endocrine tests, as well polymorphisms in genes regulating the stress hormone system, show associations with response to antidepressant treatment, these measures will need to be combined with other variables, including clinical information and other biological measures, to realize the goal of highly predictive and clinically relevant biomarkers. The glucocorticoid system is potentially of great use in predicting antidepressant response. New combinations of biomarkers including these measures should be tested to develop clinically relevant predictors.

Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90

Steroid hormone receptors are key components of mammalian stress and sex hormone systems. Many of them rely on the Hsp90 chaperone system for full function and are further fine-tuned by Hsp90-associated peptidyl-prolyl isomerases such as FK506-binding proteins 51 and 52. FK506-binding protein 51 (FKBP51) has been shown to reduce glucocorticoid receptor signalling and has been genetically associated with human stress resilience and with numerous psychiatric disorders. The peptidyl-prolyl isomerase domain of FKBP51 contains a high-affinity binding site for the natural products FK506 and rapamycin and has further been shown to convey most of the inhibitory activity on the glucocorticoid receptor. FKBP51 has therefore become a prime new target for the treatment of stress-related affective disorders that could be amenable to structure-based drug design. Here, a series of high-resolution structures of the peptidyl-prolyl isomerase domain of FKBP51 as well as a cocrystal structure with the prototypic ligand FK506 are described. These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors.

Antidepressants recruit new neurons to improve stress response regulation

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.

Stress and Affective Disorders: Animal Models Elucidating the Molecular Basis of Neuroendocrine-Behavior Interactions

Profound dysfunctions in several neuroendocrine systems have been described in patients suffering from affective disorders such as major depression. In order to elucidate the mechanisms underlying these functional alterations, animal models including mice genetically modified by either direct gene-targeting or by selective breeding approaches have been used exceedingly, revealing valuable insights into neuroendocrine pathways conserved between rodents and men. This review focuses on altered function and regulation of the hypothalamic-pituitary-adrenocortical axis, including its involvement in emotionality and stress responsiveness. In this context, the corticotropin-releasing hormone system and disturbances in glucocorticoid receptor signaling seem to be of central importance. However, changes in the expression and release patterns of vasopressin, dopamine and serotonin have also been shown to contribute to variation in emotionality, stress coping, cognitive functions and social behaviors. Affective disorders show a high degree of complexity, involving a multitude of molecular, neuroendocrine, and behavioral alterations as well as an intense gene-environment interaction, making it difficult to dissociate the primary causes from secondary consequences of the disease. Thus, interdisciplinary research, as applied in the emerging field of systems biology, involving adequate animal models and combined methodologies can significantly contribute to our understanding regarding the transmission of genetic predispositions into clinically relevant endophenotypes. It is only with deep insight into the mechanisms by which the stress hormone systems are regulated that novel treatment strategies and promising targets for therapeutic interventions can be developed in the future. Such in-depth understanding is ultimately essential to realizing our goal of predictive, preventive, and personalized medicine.

Stress as a Pathophysiological Factor in Functional Somatic Syndromes

Functional somatic syndromes (FSS) are defined by a constellation of symptoms for which after thorough medical examination no structural pathology and no proportional tissue abnormalities can be identified. Pathophysiology of these syndromes has remained elusive and treatment options are limited. Current research efforts acknowledge the importance of stress as a potential risk factor in the manifestation and maintenance of FSS. A substantial body of research has focused on psychological stress factors as well as alterations of the endocrine stress system (the hypothalamicpituitary- adrenal, HPA axis, in particular), the immune system, and the autonomic nervous system (ANS). Dysregulation of these systems might explain some of the symptoms of FSS. In this review, we describe studies reporting stress-related findings in three of the most prevalent and well-described FSS, i.e. chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), and fibromyalgia syndrome (FMS). Psychobiological processes which seem to play a role in the translation of stress into functional symptoms and syndromes are discussed.

The stress hormone system in various sleep disorders

Hypothalamic-pituitary-adrenal (HPA)-system activity is regulated by the suprachiasmatic nucleus, the primary endogenous circadian pacemaker. In addition, sleep plays an important modulatory role. However, data on HPA-system activity in sleep disorders are quite conflicting. A sensitive challenge test to assess negative feedback sensitivity of the HPA-system like the dexamethasone/corticotropin-releasing-hormone (DEX/CRH)-test has never been used so far in sleep disorders. Therefore we studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. The dynamic response of the HPA-system was assessed by the DEX/CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. After HPA-axis suppression the number of non-suppressors did not differ among groups indicating normal negative feedback sensitivity. In RLS patients ACTH levels were slightly lower compared to controls while cortisol levels were similar between groups. Following CRH stimulation we did not detect differences in ACTH- or cortisol levels and adrenocortical responsitivity to ACTH was comparable between groups. These results for the first time document normal HPA-system feedback sensitivity in various sleep disorders and suggest that abnormalities of the stress hormone system in affective disorders are unlikely due to concomitant sleep problems.

Intrahippocampal Corticosterone Response in Mice Selectively Bred for Extremes in Stress Reactivity: A Microdialysis Study

The hypothalamic-pituitary-adrenocortical (HPA) axis is one of the major stress hormone systems, and glucocorticoids (GCs) play a pivotal role in homeostatic processes throughout the body and brain. A dysregulation of the HPA axis, leading to an aberrant secretion of GCs, is associated with affective disorders such as major depression. In the present study, three mouse lines selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity were used to elucidate the temporal dynamics of intrahippocampal corticosterone (CORT) in response to a standardised stressor. In particular, we addressed the question of whether the distinct differences in HPA axis reactivity between the three mouse lines, as determined by plasma CORT measurements, are present in the central nervous system as well, and if the respective endophenotype is brought about by alterations in blood-brain barrier (BBB) functionality. We applied in vivo microdialysis in the hippocampus, demonstrating that the concentrations of CORT released from the adrenals in response to restraint stress are not only distinctly different in the plasma, but can also be found in the central nervous system, although the differences between the three mouse lines were attenuated, particularly between IR and LR animals. Additionally, a time lag of approximately 60 min was observed in all three lines regarding intrahippocampal peak concentrations of CORT after the onset of the stressor. Furthermore, we showed that the penetration and clearance of CORT in the hippocampal tissue was not affected by differences in BBB functionality because the multidrug resistance 1 P-glycoprotein (Mdr1 Pgp) was equally expressed in HR, IR and LR mice. Furthermore, we could exclude surgical damage of the BBB because peripherally-injected dexamethasone, which is a high affinity substrate for the Mdr1 Pgp and therefore restricted from entering the brain, could only be detected in the plasma and was virtually absent in the brain.

Stress Hormone Regulation: Biological Role and Translation into Therapy

Stress is defined as a state of perturbed homeostasis following endangerment that evokes manifold adaptive reactions, which are summarized as the stress response. In the case of mental stress, the adaptive response follows the perception of endangerment. Different peptides, steroids, and biogenic amines operate the stress response within the brain and also after they have been released into circulation. We focus in this review on the biological roles of corticosteroids, corticotrophin-releasing hormone (CRH), and arginine vasopressin (AVP), and we evaluate the effects of treatments directed against the actions of these hormones. CRH and AVP are the central drivers of the stress hormone system, but they also act as neuromodulators in the brain, affecting higher mental functions including emotion, cognition, and behavior. When released toward the pituitary, these central neuropeptides elicit corticotrophin into the periphery, which activates corticosteroid release from the adrenal cortex. These stress hormones are essential for the adequate adaptation to stress, but they can also evoke severe clinical conditions once persistently hypersecreted. Depression and anxiety disorders are prominent examples of stress-related disorders associated with an impaired regulation of stress hormones. We summarize the effects of drugs acting at specific targets of the stress hormone axis, and we discuss their potential use as next-generation antidepressant medications. Such treatments require the identification of patients that will optimally benefit from such specific interventions. These could be a first step into personalized medicine using treatments tailored to the specific pathology of the patients.

Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood

Behavioural profiles can be shaped by genotype and environmental factors during early phases of life. The aim of this study was to investigate whether anxiety-like behaviour, exploration and adrenocortical stress responses can be modulated by genotype and social experiences in adulthood. Male mice lacking the serotonin transporter gene which is under scrutiny for anxiety disorders were compared with heterozygous and wildtype controls. Concerning social experiences, the males of all three genotypes were provided with a winner or a loser experience in a resident-intruder paradigm on three consecutive days. Anxiety-like behaviour and exploration were recorded in the dark-light, elevated plus-maze and open-field test. To non-invasively assess adrenocortical activity, corticosterone metabolites were determined from feces. The main findings were: Repeated social experience, irrespective of winning or losing, elevated levels of anxiety-like behaviour and decreased exploration. In losers a distinct effect of genotype occurred, with homozygous knockout males showing more anxiety-like behaviour and less exploration than the other genotypes. In winners no genotype-dependent variation was found. Genotypes did not differ in basal stress hormone secretion. There was, however, a main effect of social experience with higher activation of the stress hormone system in losers than in winners. This effect was strongest in the heterozygous genotype. In conclusion, our data show that anxiety circuits retain their plasticity throughout adulthood and can be shaped by genotype and social experiences during this phase of life. Moreover, responsiveness towards negative life experiences is influenced significantly by the 5-HTT genotype.

Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding

Emotionally arousing experiences are usually well retained, an effect that depends on the release of adrenal stress hormones. Animal studies have shown that corticosterone and noradrenaline – representing the two main stress hormone systems – act in concert to enhance memory formation by actions involving the amygdala, hippocampus and prefrontal cortex (PFC). Here we test whether interactions between these two stress hormone systems also affect human memory formation as well as the associated pattern of brain activation. To this end, forty-eight male human subjects received hydrocortisone, yohimbine or both before presentation of emotional and neutral pictures. Activity in the amygdala, hippocampus and PFC was monitored with functional Magnetic Resonance Imaging (fMRI) during encoding of these stimuli, when hormonal levels were elevated. Memory performance was tested 1 week later. We investigated whether an increased level of one of the two hormone systems would lead to differential effects compared to the combined application of the drugs on brain activation and memory performance. We report that the application of cortisol led to an overall enhancing effect on recognition memory, with no significant additional effect of yohimbine. However, during encoding the brain switched from amygdala/hippocampus activation with either hormone alone, to a strong deactivation of prefrontal areas under the influence of the combination of both exogenous hormones. Although we did not find evidence that exogenous stimulation of the noradrenergic and corticosteroid systems led to significant interaction effects on memory performance in this experiment, we conclude that stress hormone levels during encoding did differentially determine the activation pattern of the brain circuits here involved.

Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

BackgroundDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.Methodology/Principle FindingsIn order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Conclusion/SignificanceThus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD.

Chronic social stress during adolescence in mice alters fat distribution in late life: Prevention by antidepressant treatment

Obesity and visceral fat accumulation are key features of the metabolic syndrome that represents one of the main health problems in western societies due to its neurovascular and cardiovascular complications. Epidemiological studies have identified chronic stress exposure as an important risk factor for the development of obesity and metabolic syndrome, but also psychiatric diseases, especially affective disorders. However, it is still unclear if chronic stress has merely transient or potentially lasting effects on body composition. Here, we investigated the effects of chronic social stress during the adolescent period on body fat composition in mice one year after the cessation of the stressor. We found that stress exposure during the adolescent period decreases subcutaneous fat content, without change in visceral fat, and consequently increases the visceral fat/subcutaneous fat ratio in adulthood. Further, we demonstrated that treatment with a selective serotonin reuptake inhibitor (paroxetine) during stress exposure prevented later effects on body fat distribution. These results from a recently validated chronic stress paradigm in mice provide evidence that stressful experiences during adolescence can alter body fat distribution in adulthood, thereby possibly contributing to an increased risk for metabolic diseases. Antidepressant treatment disrupted this effect underlining the link between the stress hormone system, metabolic homeostasis and affective disorders.

Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity

Event Abstract Back to Event Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity Chadi Touma1*, Rupert Palme2, Florian Holsboer1 and Rainer Landgraf1 1 Max Planck Institute of Psychiatry, Germany 2 University of Veterinary Medicine, Austria Affective disorders are among the most prevalent and costly diseases of the central nervous system. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions of the HPA axis, play a prominent role in the aetiology of major depression. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel the mechanisms underlying increased or decreased stress reactivity. Starting from a population of outbred mice, two breeding lines were established according to the outcome of a “stress reactivity test” (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after the stressor. Mice showing a high or a low secretion of corticosterone in the SRT were selected for the “high reactivity” (HR) and the “low reactivity” (LR) breeding line, respectively. Additionally, a third breeding line with an “intermediate reactivity” (IR) in the SRT was established. Already in the first generation, significant differences in HPA axis reactivity between HR, IR, and LR mice were observed. These differences remained stable across all subsequent generations and could be increased by selective inbreeding. Repeated testing in the SRT furthermore proved that the observed differences in stress responsiveness are already present early in life and can be regarded as a robust genetic predisposition. Emotional behaviour testing, sleep EEG measurements and morphometric, neuroendocrine, and gene expression findings also point to similarities with depressive patients. Taken together, our results indicate that distinct mechanisms influencing the function and regulation of the HPA axis seem to mediate the respective behavioural and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines are a valuable model to elucidate the molecular-genetic underpinnings of altered stress reactivity and thereby improve our understanding of affective disorders. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Touma C, Palme R, Holsboer F and Landgraf R (2009). Genes, Hormones and the Brain: Modeling Clinically Relevant Endophenotypes of Major Depression in Mice Selected for Extremes in Stress Reactivity. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.323 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Jun 2009; Published Online: 15 Jun 2009. * Correspondence: Chadi Touma, Max Planck Institute of Psychiatry, Munich, Germany, chadi.touma@uni-osnabrueck.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Google Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Google Scholar Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf PubMed Chadi Touma Rupert Palme Florian Holsboer Rainer Landgraf Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Mice selected for high versus low stress reactivity: A new animal model for affective disorders

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety-related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were 'hyperactive' in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.

CRH₁ receptor antagonists for the treatment of depression and anxiety.

From basic and clinical studies, ample evidence has emerged that abnormalities of stress hormone regulation observed in depression and anxiety are caused by elevated secretion of hypothalamic corticotropin-releasing hormone (CRH). This neuropeptide acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which has resulted in extensive validation of CRH1 receptors as a potential drug target. A number of orally available nonpeptidergic small molecules that are able to pass the blood-brain barrier have been discovered. Some of these compounds have entered clinical development. The authors summarize results from clinical studies of 2 CRH1 antagonists. One study designed as a safety and tolerability study also monitored amelioration of depression under 2 dose-escalation regimens. The compound studied, NBI-30775/R121919, was found to have a clinical profile comparable to that of paroxetine. In a second study the effect of another CRH1 antagonist, NBI-34041, on stress hormone secretion in response to a psychosocial stressor was investigated. Administration of this compound to healthy controls was found to reduce the stress-elicited secretion of stress hormones. However, neither compound impaired the CRH-induced release of adrenocorticotropic hormone and cortisol, rejecting the possibility that the stress hormone system is impaired by CRH1 antagonists. From these studies the authors conclude that both CRH1 antagonists have psychotropic effects unrelated to their neuroendocrine action, in line with behavioral data obtained from transgenic mice with CRH1 gene deletions. The psychotropic effects observed in the clinical studies underscore that CRH1 antagonists constitute a novel treatment of depression and anxiety but may also serve to prevent negative sequelae of severe stressors.