The overarching goal of this project is to describe the long-term consequences of fetal/neonatalglucocorticoid exposure on the developing hypothalamo-pituitary-adrenal (HPA) axis. It has been shownthat fetal and neonatal insults can affect the developing HPA axis, resulting in stress hyper-reactivity inadulthood. Females are more susceptible to these effects than males. Early exposure of the developingbrain to glucocorticoids is responsible for these long lasting changes in HPA function, yet the cellularmechanisms responsible for programming the memory of early glucocorticoid exposure to adult stressresponsiveness remains unknown. Such observations have implication in the study of major depressivedisorder (MOD). Clinical and preclinical studies show a causal link between the dysregulation of the HPAaxis and behavioral pathology. Furthermore, depression is prevalent in females with F:M ratios of greaterthan 2:1. Clinical studies of depressed patients show gender differences that arise at adolescence asreflected by an increased incidence of MDD in girls and decreased incidence in boys. Preliminary datapresented in this application show that the HPA axis of rodents is sexually differentiated and, if extrapolatedto humans, such a sex difference may underlie the sex differences in the prevalence of MDD.Perinatal exposure to glucocorticoids can increase the number of dying cells within the lateral PVN, infemale but not male neonates and increase expression of some pro-apoptotic genes in the neonatal brain.This raises the possibility that perinatal exposure to glucocorticoids can permanently change the function ofthe adult HPA axis by altering the numbers of some neurons within or around the PVN. Alternatively, longterm changes in gene expression may be due to altered DMA methylation as a result of neonatalglucocorticoid or gonadal steroid hormone. Studies in this application will test two hypotheses regardingthe fetal programming of adult stress responsiveness 1) That prenatal/neonatal exposure to stress causespermanent changes in the function of the HPA axis by either increasing the incidence of death in a selectneuronal phenotype in the PVN, or by causing permanent changes in gene expression in PVN neuronsthrough DNA methylation. 2) That there are sex-specific affects of fetal/neonatal glucocorticoid exposureon the developing PVN as a result of molecular interactions between GR and ER.
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