Metabolic Signals Modulate Hypothalamic‐Pituitary‐Adrenal Axis Activation During Maternal Separation of the Neonatal Mouse

Abstract

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.

Neuropeptide Y mediates the initial hypothalamic–pituitary–adrenal response to maternal separation in the neonatal mouse

“…Further, these changes were accompanied (or even preceded) by alterations in peripheral metabolic signals as glucose or ghrelin. A suppression of these metabolic signals in the periphery resulted in an attenuation of corticosterone release and prevented separation-induced gene expression changes (Schmidt et al 2006). Here, we demonstrate the same effect in NPY-deficient mice, suggesting a direct involvement of this neuropeptide in the activation of the HPA axis during maternal separation.…”

“…While a replacement of maternal care behavior (anogenital stroking) could only reverse maternal separation-induced changes in central HPA axis parameters, feeding in combination with stroking could also prevent the initial peripheral activation of the HPA axis , van Oers et al 1998. In a previous study by our group, we could show that a number of peripheral metabolic markers such as glucose, leptin, and ghrelin are markedly altered following an 8 h maternal separation (Schmidt et al 2006). In the same study, we were able to ameliorate the initial HPA axis activation due to maternal separation by glucose replacement or by antagonizing the growth hormone (GH) secretagogue receptor (i.e.…”

“…Maternally separated litters were randomly assigned to injections with either vehicle (physiological saline; SEP-veh) or the GH secretagogue receptor antagonist [D-Lys3]-GHRP-6 (SEP-GA) in a dose of 12 mg/kg body weight (dose based on Beck et al (2004) and Schmidt et al (2006)). The injection volume was always adjusted to 30 ml.…”

“…The non-separated pups were all injected with vehicle. We did not include a non-separated group treated with [D-Lys3]-GHRP-6, as we could previously show that this treatment has no effect under basal conditions during the SHRP (Schmidt et al 2006). All pups were injected subcutaneously 6 h before testing (for separated pups this was 2 h after the onset of the separation period).…”

A highly sensitive immunofluorometric assay for the measurement of aldosterone in small sample volumes: validation in mouse serum

“…Currently, there is a lack of longitudinal and systematic studies addressing adrenal gland growth and function as well as circulating aldosterone concentrations in mouse models. Plasma concentrations of corticosterone are relatively high and are therefore unproblematic to measure in mice (Weber et al 1999, Coll et al 2004, Wang et al 2004, Karpac et al 2005, Lee et al 2005, Sausbier et al 2005, Schmidt et al 2006, Davies et al 2007), whereas measurement of aldosterone can be problematic due to the low concentrations found in plasma and the limited amounts which can be collected from mice when repeated measurements must be carried out.…”