Chronic prenatal ethanol exposure alters glucocorticoid signalling in the hippocampus of the postnatal Guinea pig.

The present study tested the hypothesis that chronic prenatal ethanol exposure causes long-lasting changes in glucocorticoid signalling in postnatal offspring. Pregnant guinea pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric-sucrose/pair-feeding or water throughout gestation, and maternal saliva cortisol concentration was determined 2 h after treatment at different stages of gestation. Electrically-stimulated release of glutamate and GABA, in the presence or absence of dexamethasone, as well as glucocorticoid and mineralocorticoid receptor mRNA expression, was determined in the hippocampus and prefrontal cortex of adult offspring of treated pregnant guinea pigs. Maternal saliva cortisol concentration increased throughout pregnancy, which was associated with increased foetal plasma and amniotic fluid cortisol concentration. Ethanol administration to pregnant guinea pigs increased maternal saliva cortisol concentration during early and mid-gestation. In late gestation, ethanol administration did not increase saliva cortisol concentration above that induced by pregnancy. Chronic prenatal ethanol exposure had no effect on stimulated glutamate or GABA release, but selectively prevented dexamethasone-mediated suppression of stimulated glutamate release, and decreased expression of mineralocorticoid, but not glucocorticoid, receptor mRNA in the hippocampus of adult offspring. These data indicate that maternal ethanol administration leads to excessively increased maternal cortisol concentration that can impact negatively the developing foetal brain, leading to persistent postnatal deficits in glucocorticoid regulation of glutamate signalling in the adult hippocampus.

Central regulation of the hypothalamic-pituitary-adrenal axis during fetal development in the Guinea-pig.

We have previously shown that the foetal guinea-pig hypothalamic-pituitary-adrenal (HPA) axis is activated near the time of parturition and that this is associated with changes in limbic glucocorticoid receptors (GR) and mineralocorticoid receptors. In the present study, we hypothesized that the foetal hypothalamic paraventricular nucleus (PVN) and pituitary contribute significantly to foetal HPA drive but that these areas remain sensitive to negative feedback by circulating glucocorticoids in late gestation. However, we observed decreased corticotrophin-releasing hormone mRNA expression in the PVN and decreased pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary with advanced gestational age. The reduction in POMC mRNA expression was likely the result of negative feedback via circulating glucocorticoids because GR mRNA was unchanged during development in the foetal pituitary. Furthermore, we found that maternally administered glucocorticoids significantly decreased foetal pituitary POMC mRNA expression in a dose-dependent manner at gestational day (gd) 62 with male foetuses being more sensitive to these effects. These findings show that the foetal HPA axis remains highly sensitive to glucocorticoid feedback even as plasma adrenocorticotropic hormone and cortisol levels are elevated at the end of gestation.

Fetal glucocorticoid exposure and hypothalamo-pituitary-adrenal (HPA) function after birth.

The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Indeed, 7-10% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is effective in reducing respiratory complications. However, very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence that exposure of the fetal brain to excess glucocorticoid can have lifelong effects on neuroendocrine function and behavior. We have shown that both endogenous glucocorticoid and synthetic glucocorticoid exposure has a number of rapid effects in the fetal brain in late gestation, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback machinery after birth. Prenatal glucocorticoid manipulation also leads to modification of HPA-associated behaviors, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.

Glucocorticoids, hypothalamo-pituitary-adrenal (HPA) development, and life after birth.

Approximately 10% of women in North America are treated with synthetic glucocorticoid (sGC) between 24 and 32 weeks of pregnancy (term approximately 40 weeks), to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is highly effective in reducing the frequency of respiratory complications, and as a result, repeated course treatment has become widespread. Nothing is known about the impact of repeated sGC treatment on neuroendocrine development in the human, or if specific time windows of increased sensitivity exist. Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence from a number of species, that exposure of the fetal brain to excess glucocorticoid can have life-long effects on behaviour and neuroendocrine function. We have shown that exposure of fetuses to sGC in late gestation permanently alters HPA function in pre-pubertal, post-pubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback. Prenatal glucocorticoid exposure also leads to modification of HPA-associated behaviours and organ morphology, as well as altered regulation of other neuroendocrine systems. Permanent changes in HPA function will have a long-term impact on health, since elevated cumulative exposure to endogenous glucocorticoid has been linked to the premature onset of pathologies associated with aging.

Preferences of mice, Mus musculus, for different types of running wheel.

Mice are increasingly used in research. In particular, their wheel running is often used as a measure of activity, and as a marker of phase of circadian rhythms. Learning about the preferences of mice for different types of wheel may improve their welfare and suggest ways of increasing activity levels. Mice, Mus musculus, were given a choice between different types of running wheel by putting them in cages equipped with two wheels. Strong preferences were shown for wheels with a plastic mesh flooring, rather than the standard metal rods only. The mesh was even preferred over a solid base, although this effect was not seen in mice that had been given access only to wheels with the solid base immediately prior to the choice test. Small diameter wheels, sometimes sold as mouse wheels, were preferred less than standard-sized wheels with rods. The results suggest that types of running wheel often used in laboratories can be improved by considering the animals' preferences. The types of wheel tested here are easy to maintain and entail little additional cost, while increasing the mouse's interest in running and exercise.