RESUMO
The postnatal development of the mouse is characterized by a period of hypo-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to mild stressors. Maternal deprivation (MD) during this period can disrupt the quiescence of the HPA-axis. The present study examined the influence of strain (outbred CD1 vs. inbred C57BL/6J mice) on some central and peripheral components of the HPA-axis in neonatal mice (5-day-old) in the presence of their mother or after 24 h MD (on postnatal day 4) under basal or mild stressful conditions. In the presence of the dam, adrenal corticosterone (CORT) secretion was low in both mouse strains. Compared to CD1 mice, C57BL/6J had lower CORT levels associated with higher ACTH levels and ACTH/CORT ratio (i.e., lower adrenal sensitivity to ACTH), and higher glucocorticoid receptor (GR) mRNA expression in the paraventricular nucleus. Although MD disinhibited the HPA-axis in both strains as reflected by increased basal CORT and ACTH, we found a strain-dependent pattern. MD increased CORT more in C57BL/6J compared to CD1 mice together with a lower ACTH/CORT ratio (i.e., higher adrenal sensitivity to ACTH), while GR mRNA was no longer different in the two strains. However, this increased adrenal sensitivity in maternally deprived C57BL/6J mice was not reflected in their CORT response to a subsequent novelty stressor, possibly due to an MD-induced ceiling effect in their steroidogenic capacity. In conclusion, the immediate outcome of MD depends on the genetic background of the mother-infant dyad, suggesting that maybe also the outcome in later-life cannot be generalized.
RESUMO
Adrenal corticosterone secretion of newborn mice rapidly desensitizes to repeated maternal absence. The present study investigated the effects of novelty exposure, maternal care and genotype on this phenomenon. Maternal separation (MS) took place on postnatal days (pnd) 3-5. In Wistar rats, the degree of novelty in the MS-environment was varied by exposing pups to: (i) "home separation": pups remained in the home cage; (ii) "novel separation": pups were placed individually in a novel cage. Maternal care was recorded on pnd 1 to 4. To investigate the effect of genotype, we also examined Long Evans in the "home separation" condition. Basal and stress-induced ACTH and corticosterone levels were measured. Adrenal tyrosine hydroxylase (TH) and melanocortin receptor-2 (MCR-2) proteins served as markers for adrenal function. We show, in both rat strains, that the rise in plasma corticosterone induced by a single 8h-MS on pnd 5 was abolished, when this separation procedure had also been performed on pnd 3 and 4. Habituation to maternal absence occurred irrespective of housing conditions. However, pups in the "home separation" condition received less maternal care upon reunion than those placed in the "novel separation". These "home separation" pups appeared more responsive to a subsequent acute novelty-stressor, and their adrenal TH and MCR-2 were higher. Long Evans rats appeared more stress responsive than the Wistars, in the home separation condition. In conclusion, separation environment, maternal care and genotype do not affect adrenal desensitization to repeated 8 h-MS itself, but may modulate the adrenal stress-responsiveness of separated pups.
Assuntos
Corticosterona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Privação Materna , Estresse Psicológico/metabolismo , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Animais Recém-Nascidos , Meio Ambiente , Abrigo para Animais , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos , Ratos Long-Evans , Ratos Wistar , Receptor Tipo 2 de Melanocortina/metabolismo , Especificidade da Espécie , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
As there is little known about age-related changes in the hypothalamic-pituitary-adrenal (HPA) axis of mice, we determined the daily patterns of corticosterone secretion every 2 h, together with adrenocorticotropic hormone (ACTH) release and central HPA axis markers in the morning and evening of 3-, 9- and 16-month-old male C57BL/6J mice. We observed that: (i) corticosterone secretion showed a distinct age-related circadian pattern. During the light period this was expressed by relative hypercorticism in 9-month-old mice and relative hypocorticism in 16-month-old mice. ACTH was elevated at 16 months of age; (ii) mineralocorticoid (MR) and glucocorticoid receptor (GR) mRNA expression in the hippocampus was significantly decreased in 9-month-old mice, whereas in 16-month-old mice, expression was similar to young animals. Circadian variation was modest in all age groups; (iii) the parvocellular hypothalamic paraventricular nucleus (PVN) expressed very high vasopressin mRNA, which was subject to circadian variation in 3- and 9-month-old mice. Furthermore, significant levels of MR mRNA were expressed in the PVN. In conclusion, basal HPA axis activity and expression of its central regulatory markers are age-dependent in mice. This suggests that the capacity to adjust to environmental demands is either a function of age, or depends on different dynamics of the HPA axis.
Assuntos
Envelhecimento/fisiologia , Sistema Hipotálamo-Hipofisário/crescimento & desenvolvimento , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/crescimento & desenvolvimento , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Arginina Vasopressina/biossíntese , Peso Corporal/fisiologia , Ritmo Circadiano/fisiologia , Hormônio Liberador da Corticotropina/biossíntese , Hipocampo/metabolismo , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Hipotalâmico Paraventricular/metabolismo , RNA Mensageiro/biossíntese , Receptores de Glucocorticoides/biossíntese , Receptores de Mineralocorticoides/biossínteseRESUMO
Facioscapulohumeral muscular dystrophy (FSHD) progressively affects the facial, shoulder, and upper arm muscles and is associated with contractions of the polymorphic D4Z4 repeat array in 4q35. Recently, we demonstrated that FSHD alleles are hypomethylated at D4Z4. To study potential relationships between D4Z4 hypomethylation and both residual repeat size and clinical severity, we compared the clinical severity score with D4Z4 methylation in unrelated FSHD patients. Correcting the clinical severity score for age at examination improves the parameter to define clinical severity and provides further support for hypomethylation of FSHD alleles. However, a linear relationship between repeat size and clinical severity of the disease cannot be established. Interestingly, FSHD can be separated in two clinical severity classes: patients with residual repeat sizes of 10 to 20 kb are severely affected and show pronounced D4Z4 hypomethylation. In contrast, patients with repeat sizes of 20 to 31kb show large interindividual variation in clinical severity and D4Z4 hypomethylation. Because the majority of familial FSHD cases are represented in this interval and considering the overt variation in clinical severity in these familial cases, it thus is imperative to develop comprehensive allele-specific assays monitoring total D4Z4 methylation to investigate whether interindividual variation in D4Z4 methylation can be translated into a prognostic factor for clinical severity.
Assuntos
Cromossomos Humanos Par 4 , Variação Genética , Distrofia Muscular Facioescapuloumeral/genética , Sequências Repetitivas de Ácido Nucleico/genética , Fatores Etários , Alelos , Humanos , Modelos Lineares , Metilação , Mapeamento por RestriçãoRESUMO
In the present study, the interaction of age and apolipoprotein E (apoE)-genetic background on cognitive abilities was investigated in young (5-6 months) and aged (14-16 months) female apolipoprotein E-knockout (apoE0/0) and wild-type mice. Cognitive abilities are known to be affected by the steroid hormones corticosterone and estrogen. Therefore, we measured the activity and reactivity of the hypothalamic-pituitary-adrenal (HPA) axis expressed by circadian corticosterone concentrations and responses to novelty and controlled the regularity of the estrous cycle. Young female apoE0/0 mice acquired the water maze task and showed a similar latency and search strategy to locate the platform as young female wild-type mice. Similar corticosterone responses to novelty were observed in both genotypes. Regularity of the estrous cycle was disturbed in a small percentage of the young apoE0/0 female mice. However, in aged female apoE0/0 mice water maze performance was impaired with search strategies less persistent than in aged wild-type mice. In parallel, increased corticosterone concentrations were measured in apoE0/0 mice in response to novelty and during the circadian cycle. The percentage of mice with an irregular estrous cycle increased with age, but was comparable for apoE0/0 and wild-type mice. Thus, although disruption of the apoE gene affects the regularity of the estrous cycle in young mice, it is the enhanced corticosterone secretion, which parallels the cognitive decline in the aging female apoE0/0 mice.
Assuntos
Apolipoproteínas E/metabolismo , Transtornos Cognitivos/metabolismo , Corticosterona/sangue , Aprendizagem em Labirinto/fisiologia , Camundongos Knockout/fisiologia , Idade de Início , Animais , Apolipoproteínas E/genética , Ritmo Circadiano/fisiologia , Meio Ambiente , Ciclo Estral , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Radioimunoensaio , Tempo de Reação , NataçãoRESUMO
The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show that this contraction causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results strongly suggest that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1.
Assuntos
Cromossomos Humanos Par 4/genética , Metilação de DNA , Distrofia Muscular Facioescapuloumeral/genética , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico/genética , Feminino , Genótipo , Humanos , Masculino , LinhagemRESUMO
Character optimization methods can be used to reconstruct ancestral states at the internal nodes of phylogenetic trees. However, seldom are these ancestral states visualized collectively. Ancient Wings is a computer program that provides a novel method of visualizing the evolution of several morphological traits simultaneously. It allows users to visualize how the ventral hindwing pattern of 54 butterflies in the genus Bicyclus may have changed over time. By clicking on each of the nodes within the evolutionary tree, the user can see an animation of how wing size, eyespot size, and eyespot position relative the wing margin, have putatively evolved as a collective whole. Ancient Wings may be used as a pedagogical device as well as a research tool for hypothesis-generation in the fields of evolutionary, ecological, and developmental biology.