Molecular and cellular events within AVP and CRH neurons in the fetal PVN that regulate the hypothalamo-hypophyseal-adrenal axis (HHAA) during the final third of pregnancy are poorly defined. In sheep, fetal adrenal maturation and subsequent cortisol secretion is necessary for parturition and maturation of organs critical for neonatal survival. In years 01-05 we combined whole animal experimental paradigms and molecular techniques to dissect critical mechanisms that regulate the HHAA in sheep in the last 30-40 days gestation (dGA). By specific lesions of, or dexamethasone implants adjacent to the fetal PVN we demonstrated the importance of the fetal PVN in regulating maturation of the fetal HHAA and parturition. We propose two hypotheses: 1) gene expression and activity within AVP and CRH neurons of the fetal PVN increases immediately preceding the preparturient increase in adrenocortical function and; 2) glucocorticoid negative feedback efficacy mediated by altered expression of the glucocorticoid receptor within the fetal PVN changes at approximately 125 dGA allowing sustained expression of AVP and CRH genes despite increasing endogenous fetal cortisol secretion. We have six Specific Aims to test our hypotheses. We will examine: 1. Ontogenic changes from 100-145 dGA in: a) c-fos expression as an index of neuronal activity within AVP and CRH neurons of the fetal PVN; b) AVP and CRH gene expression within the parvocellular fetal PVN; 2. Changes in response to fetal hypoxemia in a) c-fos as an index of neuronal activity within AVP and CRH fetal PVN neurons; b) AVP and CRH gene expression in the parvocellular fetal PVN; c) POMC expression in fetal anterior pituitary corticotropes; 3. Changes in response to bilateral fetal adrenalectomy during the period 100-135 dGA in: a) c-fos expression as an index of neuronal activity within the AVP and CRH fetal PVN parvocellular component; b) AVP and CRH gene expression within fetal PVN parvocellular neurons; c) POMC gene expression within fetal anterior pituitary corticotropes; 4. Ontogenic changes from 100-145 dGA in GR expression in: a) fetal AVP and CRH neurons; b) fetal anterior pituitary corticotropes; 5. Effects of fetal adrenalectomy and physiological glucocorticoid replacement on GR expression from 100-135 dGA in: a) fetal AVP and CRH neurons; b) fetal anterior pituitary corticotropes; 6. Changes in GR expression in response to fetal hypoxemia in: a) fetal AVP and CRH neurons; b) fetal anterior pituitary corticotropes. These studies examine the maturation and regulation of the fetal PVN and anterior pituitary utilizing a combined molecular, cellular, and in vivo approach. They continue and extend knowledge of the critical role of the fetal PVN in fetal adrenal maturation and parturition that we have provided in years 01-05.
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