Postnatal Glucocorticoid Excess Due to Pituitary Glucocorticoid Receptor Deficiency: Differential Short- and Long-Term Consequences

Abstract

A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GR(POMCCre)) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GR(POMCCre) mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GR(POMCCre) mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GR(POMCCre) mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition.

Mineralocorticoid and glucocorticoid receptor-mediated control of genomic responses to stress in the brain

“…Meanwhile, generation of another GR mutant mouse with GR deleted in all POMC expressing cells (GR POMCCre ) resulted in a lack of GR immunoreactivity in the pituitary at 3 months whilst maintaining GR expression in all other regions relevant for HPA axis regulation including hippocampus and PVN (Schmidt et al, 2009). Comparing the responses of GR POMCCre and wild-type mice exposed to chronic social defeat stress (CSDS) revealed a resilience in GR POMCCre mice since the CSDS-induced increases in anxiety-like behavior and emotionality and CDSD-induced decreases in exploratory behavior were not observed in GR POMCCre mice (Wagner et al, 2011).…”

Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation

“…Thus, the loss of PVN GR activity observed in Sim1Cre-GRe3Δ mice results in severe hyperactivity of the HPA axis response and a Cushing's syndrome-like phenotype. In contrast to GR deletion in the pituitary (Schmidt et al, 2009), compensation does not occur in response to GR deletion but instead HPA axis hyperactivation persists into adulthood while circadian rhythm of GC secretion is retained.…”

“…Its expression begins during embryogenesis in the anterior pituitary and arcuate nucleus (Elkabes et al, 1989) (Hindelang et al, 1990). Mice with the POMC-Cre transgene were crossed to mice floxed for GR to delete GR in the anterior pituitary (GR POMCCre ) (Schmidt et al, 2009). The HPA axis of GR POMCCre mice evaluated at postnatal day 6 displayed reduced PVN CRH mRNA levels, but increased PVN AVP mRNA.…”

“…As would be expected, hypothalamic drive of elevated AVP activity results in increased basal plasma levels of ACTH and subsequently increased plasma cort concentrations in GR POMCCre mice compared with controls. Loss of pituitary GR also led to reduced PVN GR mRNA levels (Schmidt et al, 2009). These differences in HPA axis activity between GR POMCCre and control mice are short-lived, only occurring in the early postnatal days.…”

The Hypothalamic-Pituitary-Adrenal Axis and the Fetus

“…As would be anticipated, mice lacking pituitary GR expression manifest hypercortisolism due to impaired negative feedback inhibition; these mice have enhanced stress-coping behaviors without apparent cognitive deficits [8]. Targeted deletion of GR in peripheral and CNS noradrenergic neurons highlight the importance of GR in adrenergic chromaffin cells [9].…”