Regulation of glucocorticoid receptor mRNA and heat shock protein 70 mRNA in the developing sheep brain

Abstract

Fetal hypothalamo-pituitary-adrenal (HPA) activity increases dramatically at term in sheep, however, little is known about the regulation of glucocorticoid feedback in the developing brain. Heat shock protein 70 (hsp70) is closely associated with glucocorticoid actions within the cell. We hypothesized that there is a decrease in glucocorticoid negative feedback in the brain, near term, resulting from changes in the expression of glucocorticoid receptors (GR) and hsp70. Brains were removed at various stages of development. GR mRNA levels in the paraventricular nucleus (PVN) and cortex, and hsp70 mRNA in the PVN were determined by in situ hybridization. In the hippocampus, GR mRNA levels were measured by Northern analysis. In the PVN, GR mRNA was present by d60. GR mRNA levels reached a peak at d100-110, but then decreased significantly with progression of gestation, and were lowest at term. Hippocampal GR mRNA levels were highest on day 130 of gestation, decreasing to low levels at term. In the cerebral cortex, GR mRNA levels were expressed at high levels in all layers of the cortex by day 110 of gestation with levels decreasing to term. Hsp70 mRNA was present in both parvocellular and magnocellular regions of the PVN, and there was no significant change in late gestation. In conclusion, (1) The high levels of GR mRNA present in the PVN, hippocampus and cerebral cortex during fetal life are likely important in development of these structures at a time when circulating glucocorticoids are low. (2) Changes in GR mRNA levels in the PVN are not associated with alterations in the expression of hsp70. (3) The decrease in GR mRNA in the hippocampus and PVN in late gestation, at a time when fetal plasma cortisol is increasing, likely facilitates maintained hypothalamic drive to the pituitary corticotroph.