HORMONAL REGULATION OF BRAIN MATURATION

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The importance of the hypothalamic-pituitary-adrenocortical axis in the transition to extrauterine life is well-known. This axis potentially also exerts regulatory influences upon the developing brain. Recent evidence suggests that antenatal corticosteroid (steroid) therapy for fetal maturation reduces the incidence of intraventricular hemorrhage. Thus, this axis is most likely important in brain maturation. Nevertheless, the effects antenatal steroids on the developing brain have not been well documented. This proposal examines the hypotheses that antenatal steroids matue physiologic and improve pathophysiologic brain development. Physiologic, histlolgic, biochemical and molecular methods are combined in the following Specific Aims: Aim 1 examines the effect of antenatal steroids on blood-brain barrier (BBB) function in fetal and newborn lambs. BBB permeability is quantified by the integral technique to 14 C-alpha-aminooisobutyric acid. The hypothesis to be tested is that antenatal steroids accelerate maturation of the blood- brain barrier. Aim 2 examines the effect of steroid pretreatment on brain volume regulation in fetal, newborn and adult sheep. Brain volume, water and electrolytes, are measured by standard methods and graded osmotic stress achieved with mannitol. The hypothesis to be tested is that steroid preteatment improves brain volume regulation in fetuses and newborns. Aim 3 examines the effect of steroid pretreatment on Na+, K+-ATPase activity and specific isoform gene expression in brain and choroid plexus. We will also examine whether these increases correlate directly with maturational effects of steroids on brain volume regulation. Aim 4a examines the potential neuroprotective effects of antenatal steroids on brain ischemia in the fetus. After antenatal steroids or placebo, brain ischemia is induced by bilateral carotid artery occlusion after ligation of the vertebro-occipital anastomoses. Fetal cerebral perfusion and metabolism are measured before, after 40 minutes of ischemia, and sequentially during 48 hrs of reperfusion. Cerebrospinal fluid injury markers, brain lipid peroxidation products, histology and immunohistochemistry will define brain injury, and brain water and electolytes tissue edema. The hypothesis to be tested is that antenatal steroids attenuate brain injury in the fetus. Aim 4b examines the effect of antenatal steroids on Na+,K+-ATPase activity and gene expression in ischemic and normal brain, as in Aim 3. The hypothesis to be tested is that antenatal steroids attenuate ischemia-related decreases in Na+,K+-ATPase activity and gene expression. The proposed studies will provide important information on the effects of antenatal steroids on physiologic and pathophysiologic cerebrovascular and brain maturation.