RESUMEN
It has been shown previously (Sotnikov et al., ) that mice selectively inbred for high anxiety-related behavior (HAB) vs. low anxiety-related behavior in the elevated plus maze differentially respond to trimethylthiazoline (TMT), a synthetic fox fecal odor. However, less is known about whether environmental factors can rescue these extreme phenotypes. Here, we found that an enriched environment (EE) provided during early adolescence induced anxiolytic effects in HAB (HAB-EE) mice, rescuing their strong avoidance behavior induced by TMT. In a series of experiments, the contribution of maternal, juvenile and adolescent behavior to the anxiolytic effects elicited by EE was investigated. At the molecular level, using c-fos expression mapping, we found that the activity of the medial and basolateral amygdala was significantly reduced in HAB-EE mice after TMT exposure. We further analysed the expression of Crhr1, as its amount in the amygdala has been reported to be important for the regulation of anxiety-related behavior after EE. Indeed, in situ hybridisation indicated significantly decreased Crhr1 expression in the basolateral and central amygdala of HAB-EE mice. To further test the involvement of Crhr1 in TMT-induced avoidance, we exposed conditional glutamatergic-specific Crhr1-knockout mice to the odor. The behavioral response of Crhr1-knockout mice mimicked that of HAB-EE mice, and c-fos expression in the amygdala after TMT exposure was significantly lower compared with controls, thereby further supporting a critical involvement of Crhr1 in environmentally-induced anxiolysis. Altogether, our results indicate that EE can rescue strong avoidance of TMT by HAB mice with Crhr1 expression in the amygdala being critically involved.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/metabolismo , Ambiente Controlado , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Animales , Ansiedad/inducido químicamente , Ansiedad/genética , Encéfalo/metabolismo , Genes Inmediatos-Precoces , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Receptores de Hormona Liberadora de Corticotropina/genética , Tiazoles/toxicidadRESUMEN
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 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
The postnatal development of the mouse is characterised by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to moderate stressors. Maternal separation disinhibits this blockade of the HPA axis, but the mechanism responsible is not clear. The present study examined the influence of metabolic signals on the central and peripheral components of the HPA axis in neonatal mice aged 8 days in absence or presence of the mother. Reductions in plasma glucose and leptin as well as rapid increases in plasma ghrelin were apparent in the neonate 4 h following maternal deprivation and maximal at 8 h. In addition, maternal separation induced an increase of neuropeptide Y (NPY) mRNA expression in the arcuate nucleus, a decrease of corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus and a rise in serum corticosterone. Pharmacological manipulation of the metabolic signals attenuated the HPA response to maternal separation. Thus, the rise in plasma corticosterone induced by maternal separation was ameliorated by prevention of reduction in blood glucose or blockade of the ghrelin signalling pathway, as were the hypothalamic changes in NPY and CRH mRNAs. By contrast, leptin treatment did not affect the HPA axis response to maternal separation. Together these results suggest that metabolic signals play an important role in triggering the HPA response of the neonate to maternal separation.