The postnatal development of the hypothalamic–pituitary–adrenal axis in the mouse

Abstract

The main characteristic of the postnatal development of the stress system in the rat is the so-called stress hypo-responsive period (SHRP). Lasting from postnatal day (pnd) 4 to pnd 14, this period is characterized by very low basal corticosterone levels and an inability of mild stressors to induce an enhanced ACTH and corticosterone release. During the last years, the mouse has become a generally used animal in stress research, also due to the wide availability of genetically modified mouse strains. However, very few data are available on the ontogeny of the stress system in the mouse. This study therefore describes the postnatal ontogeny of peripheral and central aspects of the hypothalamic-pituitary-adrenal (HPA) axis in the mouse. We measured ACTH and corticosterone in blood and CRH, urocortin 3 (UCN3), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transcripts in the brain at postnatal days 1, 2, 4, 6, 9, 12, 14 and 16. Our results show that we can subdivide the postnatal development of the HPA axis in the mouse in two phases. The first phase corresponds to the SHRP in the rat and lasts from right after birth (pnd 1) until pnd 12. Basal corticosterone levels were low and novelty exposure did not enhance corticosterone or ACTH levels. This period is further characterized by a high expression of CRH in the paraventricular nucleus (PVN) of the hypothalamus. Expression levels of GR in the hippocampus and UCN3 in the perifornical area are low at birth but increase significantly during the SHRP, both reaching the highest expression level at pnd 12. In the second phase, the mice have developed past the SHRP and were now exhibiting enhanced corticosterone basal levels and a response of ACTH and corticosterone to mild novelty stress. CRH expression was decreased significantly, while expression of UCN3 and GR remained high, with a small decrease at pnd 16. The expression of MR in the hippocampus was very dynamic throughout the postnatal development of the HPA axis and changed in a time and subregion specific manner. These results demonstrate for the first time the correlation between the postnatal endocrine development of the mouse and gene expression changes of central regulators of HPA axis function.

Cortisol awakening response in infants during the first six postnatal months and its relation to birth outcome

“…In rodents, this period is characterized by a reduced HPA axis response to stressors, lasting from about postnatal day 4 to 14 (Schapiro et al, 1962;Schmidt et al, 2003). Research has not yet resolved the question of whether or not such a period of HPA hypo-responsiveness also exists in humans (Lupien et al, 2009).…”

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

“…However, also in the adult high levels of corticosterone are capable of decreasing CRH mRNA expression (Kretz et al 1999, Viau et al 1999. Further, CRH expression decreases at the end of the SHRP when basal corticosterone levels increase, indicating a very sensitive negative feedback regulation of CRH gene expression in the neonate (Schmidt et al 2003a). In mice with a genetic disruption of the CRH receptor 1 throughout the body, which are unable to induce a corticosterone response to maternal separation, CRH expression is unaltered following prolonged maternal absence (Schmidt et al 2003b).…”

“…The day of testing for all experiments was P8. At this age, the animals are in the middle of the stress hyporesponsive period (Schmidt et al 2003a). Litters remained undisturbed from the day of birth until the day of testing.…”

“…Dozens of studies over the last 60 years have demonstrated robust long-term consequences of different postnatal manipulation paradigms on neuroendocrine function, memory and behavior (Levine 1957, 1959, Zarrow et al 1972, Plotsky & Meaney 1993, Liu et al 1997. This high degree of vulnerability is generally related to the so-called stress hypo-responsive period (SHRP) that lasts from about postnatal day 1 (P1) to P12 in the mouse (Schmidt et al 2003a). During this period, basal circulating corticosterone levels are very low and mild stressors are unable to induce a peripheral corticosterone response (Levine et al 2000).…”

Glucocorticoid Hormones Decrease Proliferation of Embryonic Neural Stem Cells through Ubiquitin-Mediated Degradation of Cyclin D1

“…In the brain, GRs are present in different brain regions in both neurons and glial cells (Fuxe et al, 1985;Van Eekelen et al, 1991;Schmidt et al, 2003). The expression of MR is more restricted and mainly confined to hippocampus in the adult brain.…”