Induction of Tyrosine Hydroxylase Gene Expression by Glucocorticoids in the Perinatal Rat Brain is Age-Dependent

Abstract

Brain noradrenergic system has been implicated in early-life stress effects on adult physiology and behavior; however, the mechanisms for this relationship are not clear. Here we tested the hypothesis that stress hormones, glucocorticoids, may affect noradrenergic system activity by modulating gene expression and function of tyrosine hydroxylase (TH), the key enzyme for catecholamine synthesis, in the rat brain during perinatal life. We have shown that TH mRNA levels and enzyme activity increase in the fetal rat brainstem during the last days of pregnancy. Administration of hydrocortisone or dexamethasone to female rats on day 20 of pregnancy significantly increased TH mRNA levels (real-time PCR) and enzyme activity (DOPA accumulation after inhibition of aromatic L: -amino acid decarboxylase with NSD-1015) as well as noradrenaline concentrations in the brainstem of fetuses 6 h after the treatment. Similar glucocorticoid effects on fetal TH and noradrenaline were observed 72 h after the treatment with hydrocortisone on days 16 and 18 of pregnancy. In contrast to fetuses, no effects on the TH were revealed in the brainstem of neonatal pups after single or repeated injections of hydrocortisone or dexamethasone. TH gene expression remains at a relatively constant level in the early neonatal rat brain. The results suggest that glucocorticoids are capable of inducing TH at both transcriptional and enzyme activity levels in the brainstem of near-term fetuses.

Development of the noradrenergic system of the rat brain after prenatal exposure to corticosterone

“…We have recently found the induction of TH gene expression in the fetus brainstem by glucocorticoids, which became apparent already 6 h after a single injec tion of the hormone and was maintained for 3 days after repeated injection of glucocorticoids (Kalinina et al, 2012). The increase in the level of messenger RNA was accompanied by an increase in the activity of TH and the level of NA in the brain of 20 and 21 day old rat fetuses.…”

“…It should be noted that even a short term change in the expression of genes specific for func tioning of the neurotransmitter system during critical periods of ontogenesis causes a long term change in its activity (Dygalo et al, 2008). The period of late prena tal ontogenesis is critical for formation of the noradr energic system of the brain (Dygalo, et al, 1991a;Kreider et al, 2005;Kalinina et al, 2012), and TH defines its functional activity (Kvetnansky et al, 2009). Obviously, therefore, exposure to corticoster one in prenatal ontogenesis leads to the long lasting increase in the enzyme activity in the brainstem, con taining perikaryons of noradrenergic neurons, and in the cortex, the area of distribution of the terminals of these neurons.…”

“…At the same time, not only specific gene directed experi mental effects, but also more natural factors, like stress hormones, can change gene expression in the develop ing brain. So, recently the glucocorticoid induction of the gene of tyrosine hydroxylase (TH), the key enzyme of biosynthesis of catecholamines, including norad renaline (NA), was found in the brain of rat embryos (Kalinina et al, 2012). This fact together with data cited above makes it possible to suggest a change in the brain noradrenergic system ontogenesis after prenatal exposure to glucocorticoids.…”

Effect of dexamethasone on the expression of immediate early genes c-fos and c-jun in different regions of the neonatal brain

“…the brainstem, including the medulla oblongata and the pons (part of the brain caudal to the posterior colliculus and rostral to the foramen ovale, without the cerebellum); the hippocampus; and the prefrontal cortex, were quickly dissected. These brain regions were chosen due to the considerable difference of the temporal dynamics of their formation [2][3][4]. Animals from at least five different litters were sacrificed at each time point.…”

“…The regulation of gene expression by glucocorticoids can be mediated either by the canonical mechanism that involves the interaction of the glucocorticoid receptor (GR), a transcription factor activated by the hormone, with glucocorticoid response element (GRE) of gene promoter (GRE), or by the so-called noncanonical mechanism that involves the interaction of GR with the AP-1 complex [2]. This mechanism enables the regulation of gene expression by glucocorticoids in the absence of GRE from the respective gene promoter so that the hormone can modulate the expression of these genes as well [3,4]. In this case, the expression of target transcripts can be either enhanced or suppressed depending on the protein composition of the AP-1 complex.…”