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... Show moreThe 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. Show less
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... Show moreAdrenal 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 8 h-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. (C) 2011 Elsevier Inc. All rights reserved. Show less
Enthoven, L.; Schmidt, M.V.; Cheung, Y.H.; Mark, M.H. van der; Kloet, E.R. de; Oitzl, M.S. 2010
One of the striking characteristics of the developing neuroendocrine system of rats and mice is the stress hypo-responsive period (SHRP), i.e. low basal corticosterone secretion and the inability... Show moreOne of the striking characteristics of the developing neuroendocrine system of rats and mice is the stress hypo-responsive period (SHRP), i.e. low basal corticosterone secretion and the inability to increase corticosterone in response to mild stressors during the first 2 weeks of life. However, immediately after 24 h of deprivation from maternal care the response of the hypothalamic-pituitary-adrenal (HPA) axis to mild stressors is enhanced. This study examines in CD1 mouse pups the recovery pattern of markers of HPA axis (re)activity from maternal deprivation (once for 24 h from postnatal days (pnds) 3 to 4). As expected, deprivation induced a profound corticosterone response to novelty immediately after deprivation. In contrast, 1 day after reunion with the mother (pnd 5), this effect was abolished, lasting for at least 3 days. Basal corticosterone remained even below control levels. Corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus (PVN) was suppressed for 2 days, exceeded control levels at pnds 7 and 8, and subsequently followed the gradual decline observed in controls until pnd 12. Delayed and rather short-lasting changes were found for adrenocorticotropic hormone (low at pnd 5), and glucocorticoid receptor mRNA expression (decreased in the PVN at pnd 4, and in the hippocampal CA1 area at pnd 5). Hippocampal mineralocorticoid receptor mRNA expression was unaffected. From pnds 9 to 13, both deprived and control pups gradually emerged from the SHRP in a similar temporal pattern. In conclusion, maternal deprivation at pnd 3 augments hypo-responsiveness of corticosterone secretion to mild stress for several days, but does not affect the duration of the SHRP. Whether CRH and glucocorticoid receptor changes are cause or consequence remains to be established. Show less
An adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to... Show moreAn adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to stress. The objective of this thesis research was to examine in the mouse CD1 strain the immediate and permanent effects of an adverse early experience on the neuroendocrine stress system. For this purpose the hypothalamic-pituitary-adrenal (HPA) axis was examined of mouse pups that were refrained from maternal care, a laboratory model for neglect mimicking aspects of abuse. The data show that the infants__ stress response system readily adapts to daily repeated 8 hours of maternal separation, but that it continues to respond to a novelty stressor. The rapid adaptation to repeated maternal absence seems rather due to the ability to predict return of the mother than to adjust metabolism to episodic food deprivation. If maternal separation was extended to a single episode of 24 hours the immediate outcome was more profound but transient, although subtle effects on stress reactions and cognitive performance did persist. The findings demonstrate the amazing plasticity of the newborn brain and provide a basis to study the mechanistic underpinning of vulnerability or resilience to psychopathology. Show less
