RESUMO
RATIONALE: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. OBJECTIVES: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. METHODS: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2â years (1â year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. MEASUREMENTS AND MAIN RESULTS: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2â years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. CONCLUSIONS: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.
Assuntos
Asma , Eosinofilia , Alérgenos , Biomarcadores , Antígenos CD28/genética , Eosinófilos , Humanos , Imunoglobulina E , Interleucina-13 , Interleucina-5 , Lipopolissacarídeos , Longevidade , FenótipoRESUMO
BACKGROUND: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma. METHODS: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models. RESULTS: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA+ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA+ memory B-cells significantly correlated with clinical features of SAD such as exacerbations. CONCLUSIONS: With this study we demonstrate for the first time a significant association of increased IgA+ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.
Assuntos
Asma , Adulto , Humanos , Espirometria , Oscilometria , Sistema Respiratório , Imunoglobulina ARESUMO
In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca(2+) signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders.
Assuntos
Proteínas de Transporte/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Hipocampo/metabolismo , Estresse Psicológico/complicações , Análise de Variância , Animais , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Transtornos Cognitivos/terapia , Dexametasona/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Terapia Genética , Vetores Genéticos/genética , Glucocorticoides/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas de Arcabouço Homer , Imunoprecipitação , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Reconhecimento Psicológico , Recompensa , Transdução de Sinais/fisiologia , Percepção Espacial/efeitos dos fármacos , Tiazóis/farmacologiaRESUMO
Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition.
Assuntos
Cognição/fisiologia , Sinapses/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Actinas/metabolismo , Animais , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Genes Supressores de Tumor , Células HEK293 , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuritos/metabolismo , Neuritos/ultraestrutura , Ligação Proteica , Estresse Fisiológico , Proteínas Supressoras de Tumor/genéticaRESUMO
Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1 knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1 in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1 deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF1 signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
Assuntos
Transtornos Cognitivos/fisiopatologia , Hormônio Liberador da Corticotropina/fisiologia , Prosencéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular Neuronais/metabolismo , Transtornos Cognitivos/complicações , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Hipocampo/citologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Comportamento Espacial/fisiologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/psicologiaRESUMO
Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.
Assuntos
Testes Genéticos/métodos , Hipocampo/metabolismo , Individualidade , Memória de Curto Prazo/efeitos dos fármacos , Receptores de AMPA/metabolismo , Estresse Psicológico/metabolismo , Animais , Corticosterona/sangue , Transtorno Depressivo Maior/etiologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise Serial de Proteínas/métodos , Receptores de AMPA/agonistas , Receptores de AMPA/genética , Resiliência Psicológica/efeitos dos fármacos , Fatores de Risco , Estresse Psicológico/sangue , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Sulfonamidas/farmacologiaRESUMO
Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders.
Assuntos
Dendritos/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Prosencéfalo/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Estresse Psicológico/metabolismo , Análise de Variância , Animais , Western Blotting , Peso Corporal/genética , Moléculas de Adesão Celular/metabolismo , Dominação-Subordinação , Hibridização In Situ , Masculino , Camundongos , Camundongos Transgênicos , Nectinas , Neurônios/metabolismo , Estresse Psicológico/genéticaRESUMO
Age-related cognitive decline is one of the major aspects that impede successful aging in humans. Environmental factors, such as chronic stress, can accelerate or aggravate cognitive deficits during aging. While there is abundant evidence that chronic stress directly affects cognitive performance, the lasting consequences of stress exposures during vulnerable developmental time windows are largely unknown. This is especially true for the adolescent period, which is critical in terms of physical, sexual, and behavioral maturation. Here we used chronic social stress during adolescence in male mice and investigated the consequences of this treatment on cognitive performance during aging. We observed a substantial impairment of spatial memory, but not other memory domains, 12 months after the end of the stress period. This hippocampus-dependent cognitive dysfunction was supported by concomitant impairment in LTP induction in CA1 neurons in 15-month-old animals. Further, we observed a decrease of hippocampal BDNF mRNA and synaptophysin immunoreactivity, suggesting plasticity and structural alterations in formerly stressed mice. Finally, we identified expression changes of specific neurotransmitter subunits critically involved in learning and memory, specifically the NMDA receptor subunit NR2B. Taken together, our results identify possible molecular mechanisms underlying cognitive impairment during aging, demonstrating the detrimental impact of stress during adolescence on hippocampus-dependent cognitive function in aged mice.
Assuntos
Envelhecimento/fisiologia , Transtornos Cognitivos/etiologia , Hipocampo/fisiopatologia , Meio Social , Comportamento Espacial/fisiologia , Estresse Psicológico/complicações , Fatores Etários , Envelhecimento/metabolismo , Análise de Variância , Animais , Western Blotting , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Eletrofisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Masculino , Rememoração Mental , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Reconhecimento Psicológico/fisiologia , Percepção Espacial , Estatísticas não Paramétricas , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Sinaptofisina/metabolismoRESUMO
Identifying molecular targets that are able to buffer the consequences of stress and therefore restore brain homeostasis is essential to develop treatments for stress-related disorders. Down-regulated in renal cell carcinoma 1 (DRR1) is a unique stress-induced protein in the brain and has been recently proposed to modulate stress resilience. Interestingly, DRR1 shows a prominent expression in the limbic system of the adult mouse. Here, we analyzed the neuroanatomical and cellular expression patterns of DRR1 in the adult mouse brain using in situ hybridization, immunofluorescence and Western blot. Abundant expression of DRR1 mRNA and protein was confirmed in the adult mouse brain with pronounced differences between distinct brain regions. The strongest DRR1 signal was detected in the neocortex, the CA3 region of the hippocampus, the lateral septum and the cerebellum. DRR1 was also present in circumventricular organs and its connecting regions. Additionally, DRR1 was present in non-neuronal tissues like the choroid plexus and ependyma. Within cells, DRR1 protein was distributed in a punctate pattern in several subcellular compartments including cytosol, nucleus as well as some pre- and postsynaptic specializations. Glucocorticoid receptor activation (dexamethasone 10 mg/kg s.c.) induced DRR1 expression throughout the brain, with particularly strong induction in white matter and fiber tracts and in membrane-rich structures. This specific expression pattern and stress modulation of DRR1 point to a role of DRR1 in regulating how cells sense and integrate signals from the environment and thus in restoring brain homeostasis after stressful challenges.
Assuntos
Encéfalo/metabolismo , Receptores de Glucocorticoides/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Substância Cinzenta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/agonistas , Substância Branca/metabolismoRESUMO
Understanding the molecular mechanisms by which stress is translated into changes in complex behavior may help to identify novel treatment strategies for stress-associated psychiatric disorders. The tumor suppressor gene down-regulated in renal cell carcinoma 1 (DRR1) was recently characterized as a new molecular link between stress, synaptic efficacy and behavioral performance, most likely through its ability to modulate actin dynamics. The lateral septum is one of the brain regions prominently involved in the stress response. This brain region features high DRR1 expression in adult mice, even under basal conditions. We therefore aimed to characterize and dissect the functional role of septal DRR1 in modulating complex behavior. DRR1 protein expression was shown to be expressed in both neurons and astrocytes of the lateral septum of adult mice. Septal DRR1 mRNA expression increased after acute defeat stress and glucocorticoid receptor activation. To mimic the stress-induced DRR1 increase in the lateral septum of mice, we performed adenovirus-mediated region-specific overexpression of DRR1 and characterized the behavior of these mice. Overexpression of DRR1 in the septal region increased sociability, but did not change cognitive, anxiety-like or anhedonic behavior. The observed changes in social behavior did not involve alterations of the expression of vasopressin or oxytocin receptors, the canonical social neuropeptidergic circuits of the lateral septum. In summary, our data suggest that the stress-induced increase of DRR1 expression in the lateral septum could be a protective mechanism to buffer or counterbalance negative consequences of stress exposure on social behavior.
Assuntos
Comportamento Animal , Transtornos Mentais/genética , Comportamento Social , Proteínas Supressoras de Tumor/fisiologia , Actinas/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ligação Proteica , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologiaRESUMO
Exposure to chronic stress during developmental periods is a risk factor for a number of psychiatric disorders. While the direct effects of stress exposure have been studied extensively, little is known about the long-lasting effects and the interaction with ageing. The same holds true for the treatment with selective serotonin reuptake inhibitors (SSRIs), which have been shown to prevent or reverse some stress-induced effects. Here, we studied the direct and long-lasting impact of chronic social stress during adolescence and the impact of chronic treatment with the SSRI paroxetine in adulthood and aged animals. Therefore, male CD1 mice at the age of 28 days were subjected to 7 weeks of chronic social stress. Treatment with paroxetine was performed per os with a dosage of 20 mg/g BW. We were able to reverse most of the effects of chronic social stress in adult mice (4 months old) and to some extend in aged animals (15 months old) with the SSRI treatment. Especially the regulation of the HPA axis seems to be affected in aged mice with a shift to the use of vasopressin. Our results demonstrate that chronic stress exposure and antidepressant treatment at the end of the developmental period can have a significant and long-lasting impact, highly relevant for healthy ageing.
Assuntos
Envelhecimento , Paroxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Isolamento Social/psicologia , Estresse Psicológico/tratamento farmacológico , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Arginina Vasopressina/genética , Arginina Vasopressina/metabolismo , Peso Corporal/efeitos dos fármacos , Doença Crônica , Corticosterona/sangue , Hormônio Liberador da Corticotropina/sangue , Hormônio Liberador da Corticotropina/genética , Dexametasona , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Estudos Longitudinais , Masculino , Camundongos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/sangue , Timo/efeitos dos fármacosRESUMO
Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.
Assuntos
Moléculas de Adesão Celular/fisiologia , Espinhas Dendríticas/metabolismo , Hipocampo/fisiopatologia , Memória/fisiologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Transdução de Sinais/fisiologia , Estresse Psicológico , Animais , Comportamento Animal/fisiologia , Moléculas de Adesão Celular/antagonistas & inibidores , Hormônio Liberador da Corticotropina/fisiologia , Espinhas Dendríticas/patologia , Regulação para Baixo/genética , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nectinas , Prosencéfalo/patologia , Prosencéfalo/fisiologia , Transdução de Sinais/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Regulação para Cima/genéticaRESUMO
Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.
Assuntos
Paroxetina/uso terapêutico , Comportamento Social , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Antidepressivos de Segunda Geração/uso terapêutico , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/psicologia , Resultado do TratamentoRESUMO
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Assuntos
Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/fisiopatologia , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico , Proteínas de Ligação a Tacrolimo/metabolismo , Análise de Variância , Animais , Corticosterona/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Regulação da Expressão Gênica/genética , Proteínas de Choque Térmico HSP90/metabolismo , Locomoção/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia , Natação/psicologia , Proteínas de Ligação a Tacrolimo/deficiênciaRESUMO
The incidence of chronic stress is frequently related to the development of psychiatric disorders like depression. The hypothalamic-pituitary-adrenal (HPA) axis is a major physiological system that mediates the stress response. Tight HPA axis regulation through negative feedback mechanisms is essential for health and environmental adaptation. This feedback regulation acts in part through the glucocorticoid receptor (GR) on several organizational levels, including the pituitary, the hypothalamus and the hippocampus. However, the precise role of the different anatomical structures, specifically the pituitary, in HPA axis regulation is yet largely unknown. Here, we show that a conditional pituitary GR knockout is not necessarily detrimental for the animal's ability to cope with chronic stress situations. Mice with a deletion of the GR at the pituitary (GR(POMCCre)) were subjected to 3 weeks of chronic social defeat stress. We analyzed both the behavioral and neuroendocrine phenotype as well as the central nervous system expression of genes involved in HPA axis function in these animals. Our results show a more resilient phenotype of GR(POMCCre) mice with respect to anxiety-related behavior and neuroendocrine parameters compared to stressed wild type animals. In light of the previously reported high corticosterone levels during postnatal development in GR(POMCCre) mice, our findings suggest that adverse early life events may have beneficial developmental effects on the organism to improve stress coping later in life.
Assuntos
Hipófise/metabolismo , Receptores de Glucocorticoides/genética , Estresse Psicológico/genética , Adaptação Psicológica/fisiologia , Animais , Comportamento Animal , Doença Crônica , Deleção de Genes , Predisposição Genética para Doença , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/fisiologia , Especificidade de Órgãos/genética , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Chronic stress has been found to be a major risk factor for various human pathologies. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated via, among others, the glucocorticoid receptor (GR). The activity of the GR is modulated by a variety of proteins, including the co-chaperone FK506 binding protein 51 (FKBP5). Although FKBP5 has been associated with risk for affective disorders and has been implicated in GR sensitivity, previous studies focused mainly on peripheral blood, while information about basal distribution and induction in the central nervous system are sparse. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we describe the basal expression pattern of Fkbp5 mRNA in the brain of adult male mice and show the induction of Fkbp5 mRNA via dexamethasone treatment or different stress paradigms. We could show that Fkbp5 is often, but not exclusively, expressed in regions also known for GR expression, for example the hippocampus. Furthermore, we were able to induce Fkbp5 expression via dexamethasone in the CA1 and DG subregions of the hippocampus, the paraventricular nucleus (PVN) and the central amygdala (CeA). Increase of Fkbp5 mRNA was also found after restrained stress and 24 hours of food deprivation in the PVN and the CeA, while in the hippocampus only food deprivation caused an increase in Fkbp5 mRNA. CONCLUSIONS/SIGNIFICANCE: Interestingly, regions with a low basal expression showed higher increase in Fkbp5 mRNA following induction than regions with high basal expression, supporting the hypothesis that GR sensitivity is, at least partly, mediated via Fkbp5. In addition, this also supports the use of Fkbp5 gene expression as a marker for GR sensitivity. In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain.
Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica , Proteínas de Ligação a Tacrolimo/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Dexametasona/farmacologia , Privação de Alimentos , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genéticaRESUMO
The postnatal development of the mouse is characterized by a stress hypo-responsive period (SHRP), where basal corticosterone levels are low and responsiveness to mild stressors is reduced. Maternal separation is able to disrupt the SHRP and is widely used to model early trauma. In this study we aimed at identifying of brain systems involved in acute and possible long-term effects of maternal separation. We conducted a microarray-based gene expression analysis in the hypothalamic paraventricular nucleus after maternal separation, which revealed 52 differentially regulated genes compared to undisturbed controls, among them are 37 up-regulated and 15 down-regulated genes. One of the prominently up-regulated genes, angiotensinogen, was validated using in-situ hybridization. Angiotensinogen is the precursor of angiotensin II, the main effector of the brain renin-angiotensin system (RAS), which is known to be involved in stress system modulation in adult animals. Using the selective angiotensin type I receptor [AT(1)] antagonist candesartan we found strong effects on CRH and GR mRNA expression in the brain and ACTH release following maternal separation. AT(1) receptor blockade appears to enhance central effects of maternal separation in the neonate, suggesting a suppressing function of brain RAS during the SHRP. Taken together, our results illustrate the molecular adaptations that occur in the paraventricular nucleus following maternal separation and contribute to identifying signaling cascades that control stress system activity in the neonate.
RESUMO
A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GR(POMCCre)) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GR(POMCCre) mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GR(POMCCre) mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GR(POMCCre) mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition.
Assuntos
Adaptação Psicológica/fisiologia , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais Recém-Nascidos/metabolismo , Glucocorticoides/metabolismo , Hipófise/metabolismo , Receptores de Glucocorticoides/deficiência , Animais , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Retroalimentação Fisiológica/fisiologia , Deleção de Genes , Antagonistas de Hormônios/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mifepristona/farmacologia , Modelos Animais , Núcleo Hipotalâmico Paraventricular/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Vasopressinas/metabolismoRESUMO
The period of adolescence is characterized by a high vulnerability to stress and trauma, which might result in long-lasting consequences and an increased risk to develop psychiatric disorders. Using a recently developed mouse model for chronic social stress during adolescence, we studied persistent neuroendocrine and behavioral effects of chronic social stress obtained 12 months after cessation of the stressor. As a reference, we investigated immediate effects of chronic stress exposure obtained at the end of the chronic stress period. Immediately after the 7 week chronic stress period stressed animals show significantly increased adrenal weights, decreased thymus weight, increased basal corticosterone secretion and a flattened circadian rhythm. Furthermore, stressed animals display an increased anxiety-like behavior in the elevated plus maze and the novelty-induced suppression of feeding test. Hippocampal mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) mRNA levels were significantly decreased. To investigate persistent consequences of this early stressful experience, the same parameters were assessed in aged mice 12 months after the cessation of the stressor. Interestingly, we still found differences between formerly stressed and control mice in important stress-related parameters. MR expression levels were significantly lower in stressed animals, suggesting lasting, possibly epigenetic alterations in gene expression regulation. Furthermore, we observed long-term behavioral alterations in animals stressed during adolescence. Thus, we could demonstrate that chronic stress exposure during a crucial developmental time period results in long-term, persistent effects on physiological and behavioral parameters throughout life, which may contribute to an enhanced vulnerability to stress-induced diseases.
Assuntos
Comportamento Animal/fisiologia , Corticosterona/sangue , Hipocampo/metabolismo , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico/fisiopatologia , Glândulas Suprarrenais/anatomia & histologia , Fatores Etários , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Doença Crônica , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Seguimentos , Masculino , Camundongos , Tamanho do Órgão , RNA Mensageiro/análise , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/genética , Estresse Psicológico/complicações , Timo/anatomia & histologia , Fatores de TempoRESUMO
The function of the hypothalamic-pituitary-adrenal (HPA) axis of the neonatal mouse or rat is characterized by a period of quiescence, where mild stimuli are unable to elicit a pronounced increase in circulating corticosterone. A disruption of this period by maternal separation has been shown to result in a variety of long-term consequences, including neuroendocrine and behavioral disturbances. We have recently shown that peripheral metabolic markers like glucose or ghrelin are altered by maternal separation and that these changes precede the effects on corticosterone secretion. In the current study, we investigated whether the initial activation of the HPA axis is mediated via neuropeptide Y (NPY). To test this hypothesis, we studied the effects of an 8 h maternal separation in NPY-deficient mice. In addition, we compared the effect of the genotype with the previously described pharmacological effect of a ghrelin receptor antagonist. We could show that the peripheral response to maternal separation is decreased in NPY heterozygous and homozygous animals. In addition, maternal separation effects on corticotropin releasing hormone and glucocorticoid receptor expression in the brain were prevented in NPY-deficient pups. These effects were similar to a pharmacological ghrelin receptor blockade. We conclude that metabolic signals via an NPY-mediated pathway play a crucial role in activating the stress system of the neonatal mouse.