The ontogeny of the neuroendocrine response to endotoxin

Abstract

During development, the hypothalamic–pituitary–adrenal (HPA) axis is normally hyporesponsive between postnatal days (pnd) 4 and 14. This interval has been designated as the stress-hyporesponsive period (SHRP). Recent evidence indicates that the neonate can respond to selective stimuli, i.e., exposure to immune signals. The purpose of this study was to investigate the neural correlates of the neonatal stress axis in response to a stimulus that activates the pituitary–adrenal hormones. Thus, lipopolysaccharide (LPS) was administered to neonates at three ages (pnd 6, 12, and 18) during or after the SHRP. In an effort to understand the neonatal hypothalamic paraventricular nucleus (PVN) response to an endotoxin, we measured c- fos immunoreactivity and corticotrophin-releasing hormone (CRH) gene expression. At all ages tested, there was an increase in ACTH and corticosterone (CORT) following LPS compared to controls. During the SHRP, LPS treatment resulted in a marked increase in Fos-positive cells in the PVN, whereas a saline injection had no effect. However, at pnd 18, both LPS and a saline injection elicited equivalent PVN Fos expression. In contrast to the effect on Fos, LPS and a saline injection decreased CRH mRNA at pnd 6 and 12. Outside the SHRP, LPS resulted in an increase in CRH gene expression relative to saline-injected controls. Thus, while the LPS-induced activation of Fos protein and plasma hormones were concordant, CRH mRNA did not positively correlate with the peripheral response. This suggests that the SHRP is not absolute, and the brain is responsive to some stimuli during this period.