Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice

Abstract

Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment, and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as postnatal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at postnatal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus

“…Given that deletion of Fkbp5 in the PVN mimics the previously described phenotype of Fkbp5 KO mice 21 , with regard to their basal neuroendocrine profile and HPA axis function, our data illustrate that the functional contribution of Fkbp5 to HPA axis chronic stress situation 29,30 . Interestingly, the results of our Fkbp5 PVN OE cohort are comparable to the neuroendocrine effect of GR deletion in the PVN 31 . The consequence of a heightened Fkbp5 expression in the PVN is two-fold.…”

Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering

“…However, additional multiple pathways likely exist that show developmental changes (Hostinar et al, 2014). In adults, the HPA axis is controlled through multiple levels within the brain and we speculate that social buffering potentially attenuates CORT release through many of these levels of control (Herman et al, 2003; Herman, Ostrander, Mueller, & Figueiredo, 2005; Herman et al, 1996; Herman, Tasker, Ziegler, & Cullinan, 2002; Laryea, Arnett, & Muglia, 2015; Panagiotakopoulos & Neigh, 2014). Our assessment of the changing neural network underlying maternal odor processing across development provides novel insight into potential mechanisms underlying social buffering throughout development.…”

Early life adversities or high fat diet intake reduce cognitive function and alter BDNF signaling in adult rats: Interplay of these factors changes these effects

“…Key signaling molecules of the HPA axis, as the glucocorticoid receptor (GR) and corticotrophin‐releasing hormone (CRH) receptor, are susceptible to environment influences. Some studies show that HFD intake alters some mediators of HPA axis, including GR expression, and post‐stress plasma corticosterone levels in rats (Abildgaard et al, 2014; Auvinen et al, 2012; Laryea et al, 2015; McNeilly et al, 2015). In our study, however, no significant differences in glucocorticoid receptor (GR) immunocontent in the adult prefrontal cortex were found between groups.…”