RESUMEN
Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from hypothesis-free animal experiments with data from a genetic association study in depression. Comparing genes regulated by chronic paroxetine treatment in the mouse hippocampus with genes showing nominally significant association with antidepressant treatment response in two pharmacogenetic studies, the activin pathway was the only one to show this dual pattern of association and therefore selected as a candidate. We examined the regulation of activin A and activin receptor type IA mRNA following antidepressant treatment. We investigated the effects of stereotaxic infusion of activin into the hippocampus and the amygdala in a behavioural model of depression. To analyse whether variants in genes in the activin signalling pathway predict antidepressant treatment response, we performed a human genetic association study. Significant changes in the expression of genes in the activin signalling pathway were observed following 1 and 4 weeks of treatment. Injection of activin A into the hippocampus exerts acute antidepressant-like effects. Polymorphisms in the betaglycan gene, a co-receptor mediating functional antagonism of activin signalling, significantly predict treatment outcome in our system-wide pharmacogenetics study in depression. We provide convergent evidence from mouse and human data that genes in the activin signalling pathway are promising novel candidates involved in the neurobiogical mechanisms underlying antidepressant mechanisms of action. Further, our data suggest this pathway to be a target for more rapid-acting antidepressants in the future.
Asunto(s)
Activinas , Antidepresivos , Encéfalo , Trastorno Depresivo , Paroxetina/farmacología , Proteoglicanos/genética , ARN Mensajero/análisis , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Activinas Tipo I/genética , Receptores de Activinas Tipo I/metabolismo , Activinas/genética , Activinas/metabolismo , Activinas/farmacología , Adulto , Anciano , Amígdala del Cerebelo/efectos de los fármacos , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Giro Dentado/efectos de los fármacos , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido Simple , Transducción de SeñalRESUMEN
Major depression is one of the most prevalent stress-related psychiatric diseases. Next to environmental influences such as chronic social stress, gender is among the strongest risk factors for major depression, with women having a twice as high risk to develop the disease compared to men. While there is abundant literature on the effects of chronic social stress in male rodents, there is a serious lack of information on gender-specific effects. Especially in mice, which due to the wide availability of transgenic lines offer a unique opportunity to study gene x environment interactions, there is no existing model of chronic social stress that is applicable to both sexes. We here describe the effects of chronic social stress based on the disruption of the social network in a group-housed situation in female mice, a model that was recently described and validated for male mice. In this model, the group composition of the mice is changed twice per week for a period of 7 weeks, covering the adolescent and early adulthood period. We observed that housing in an unpredictable social environment resulted in chronic stress in female mice. The observed effects, which included increased adrenal weight, decreased thymus weight, increased corticosterone levels, and increased anxiety-like behavior, were very similar to the described effects of this paradigm in male mice. In addition, we observed a distinct expression of stress system-related genes in female mice following chronic stress exposure. Our results validate this model as a suitable approach to study chronic social stress in female mice and open up the opportunity to use this model with transgenic or knockout mouse lines.
Asunto(s)
Medio Social , Estrés Psicológico/psicología , Hormona Adrenocorticotrópica/sangre , Animales , Ansiedad/psicología , Arginina Vasopresina/biosíntesis , Arginina Vasopresina/genética , Peso Corporal/fisiología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/biosíntesis , Hormona Liberadora de Corticotropina/genética , Modelos Animales de Enfermedad , Conducta Alimentaria/fisiología , Femenino , Expresión Génica , Jerarquia Social , Hibridación in Situ , Masculino , Ratones , Actividad Motora/fisiología , Tamaño de los Órganos/fisiología , Receptores de Gonadotropina/biosíntesis , Receptores de Gonadotropina/genética , Caracteres SexualesRESUMEN
Chronic stress is a key risk factor for a variety of diseases, including depression. There is a large degree of individual variation in the ability to recover successfully from a chronic stress exposure, but the determinants of this individual stress susceptibility are still poorly understood. We recently developed a novel mouse paradigm for chronic social stress during adolescence, which closely mimics the human condition of chronic social stress in respect to construct, face and predictive validity. By applying this chronic stress model to a large number of animals we aimed at identifying individuals that are either resilient or vulnerable to the persistent effects of chronic social stress exposure. Animals showing markedly elevated basal corticosterone levels 5 weeks following the end of the stress paradigm were considered "vulnerable", whereas individuals recovering quickly and being indistinguishable from controls were classified as "resilient". Stress vulnerability was associated with an increased level of corticotropin-releasing hormone in the paraventricular nucleus, decreased hippocampal mineralocorticoid receptor expression as well as increased anxiety- and depression-like behavior compared to resilient and control animals. In summary, we show that by using a large cohort of animals it is possible to select individuals that are vulnerable or resilient to the lasting effects of chronic social stress. The vulnerable phenotype mimics many aspects of stress-related human affective disorders and this may be used as a novel approach to study depression in an animal model, ultimately contributing to a better understanding and treatment of stress-related disorders.
Asunto(s)
Encéfalo/metabolismo , Corticosterona/sangre , Depresión/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/metabolismo , Conducta Social , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Animales , Ansiedad/metabolismo , Conducta Animal , Peso Corporal , Hormona Liberadora de Corticotropina/metabolismo , Masculino , Ratones , Ratones Endogámicos , Tamaño de los Órganos , Fenotipo , Receptores de Mineralocorticoides/metabolismo , Factores de TiempoRESUMEN
The importance of restraining stress-induced activation of the hypothalamic-pituitary-adrenocortical (HPA) system within tolerable limits requires efficient mechanisms for feedback inhibition. Recently, central corticotrophin-releasing hormone (CRH) receptor type 1 (CRHR1) has been shown to mediate HPA system feedback inhibition. To date, most of the data regarding stress-associated expression changes of CRHR1 and CRHR2 mRNA and their ligand CRH have been generated in rats. Taken considerable species differences into consideration, and with the growing importance of transgenic mice, a systematic analysis of the time course of expression changes of CRH and its two receptors in the mouse brain is needed to provide more insight into the regulation of the HPA system, both under physiological and pathophysiological conditions in this species. We analysed in detail the time course of expression changes of CRH, CRHR1 and CRHR2 mRNA after of restraint stress in mice in stress-relevant brain regions (paraventricular nucleus, hippocampus, neocortex). We could show a rapid, strong and long-lasting decrease in cortical and hippocampal CRHR1 mRNA expression after stress, whereas CRHR2 mRNA increased in the same neuroanatomical areas. In situ hybridisation analyses could be further confirmed at the protein level by CRH receptor autoradiography with changes in CRH binding that persisted even 7 days after a single episode of restraint stress. Our observation that stress has opposing effects on CRHR1 and CRHR2 neuronal systems supports the idea that regulation of the relative contribution of the two CRH receptors to brain CRH pathways may be essential in coordinating physiological responses to stress. We further hypothesise that the sustained alteration of CRH receptor expression and binding after a single episode of stress could mediate the long-term effects of stress on neuroendocrine function and emotional regulation.
Asunto(s)
Encéfalo/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Restricción Física , Estrés Psicológico , Animales , Autorradiografía , Encéfalo/anatomía & histología , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipotálamo-Hipofisario/fisiopatología , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Sistema Hipófiso-Suprarrenal/fisiología , Sistema Hipófiso-Suprarrenal/fisiopatología , Ratas , Receptores de Hormona Liberadora de Corticotropina/genéticaRESUMEN
Chronic stress is widely regarded as a key risk factor for a variety of diseases. A large number of paradigms have been used to induce chronic stress in rodents. However, many of these paradigms do not consider the etiology of human stress-associated disorders, where the stressors involved are mostly of social nature and the effects of the stress exposure persist even if the stressor is discontinued. In addition, many chronic stress paradigms are problematic with regard to stress adaptation, continuity, duration and applicability. Here we describe and validate a novel chronic social stress paradigm in male mice during adolescence. We demonstrate persistent effects of chronic social stress after 1 week of rest, including altered adrenal sensitivity, decreased expression of corticosteroid receptors in the hippocampus and increased anxiety. In addition, pharmacological treatments with the antidepressant paroxetine (SSRI) or with the corticotropin-releasing hormone receptor 1 antagonist DMP696 were able to prevent aversive long-term consequences of chronic social stress. In conclusion, this novel chronic stress paradigm results in persistent alterations of hypothalamus-pituitary-adrenal axis function and behavior, which are reversible by pharmacological treatment. Moreover, this paradigm allows to investigate the interaction of genetic susceptibility and environmental risk factors.
Asunto(s)
Corticosterona/sangre , Conducta Exploratoria/fisiología , Receptores de Esteroides/metabolismo , Conducta Social , Estrés Psicológico/fisiopatología , Adaptación Fisiológica , Adaptación Psicológica , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/sangre , Factores de Edad , Análisis de Varianza , Animales , Antidepresivos de Segunda Generación/uso terapéutico , Enfermedad Crónica , Modelos Animales de Enfermedad , Jerarquia Social , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Paroxetina/uso terapéutico , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicologíaRESUMEN
Many behavioural tests in rodents are based on the premise that basal locomotor activity of the animals is similar between the tested groups. The measurement of basal home cage activity is therefore an essential parameter, that should be included in all studies which employ tests of anxiety or cognition. Currently available systems for the assessment of home cage locomotion are often complex and expensive. Here we describe and validate a novel, simple and cost-efficient apparatus for the assessment of basic home cage locomotor activity in rodents. Circadian dark-light activity patterns can be reliably obtained with the home cage activity counter. Furthermore, changes in locomotion induced by novelty or pharmacological treatment were reliably and sensitively detected by the apparatus. Thus, the here presented home cage activity counter can be used for the measurement of basal home cage locomotor activity.
Asunto(s)
Actividad Motora/fisiología , Aclimatación/efectos de los fármacos , Animales , Dextroanfetamina/farmacología , Maleato de Dizocilpina/farmacología , Ambiente , Diseño de Equipo , Vivienda para Animales , Masculino , Ratones , Actividad Motora/efectos de los fármacosRESUMEN
The current model for delivery of prenatal care was developed more than 100 years ago. Evidence suggests that this model is no longer appropriate for meeting national health objectives or for meeting the needs of a diverse population of pregnant women. This article provides a historical overview of prenatal care; describes the current system for care delivery and problems associated with it; and suggests strategies for transforming care into an effective, comprehensive model.