HORMONAL REGULATION OF BRAIN MATURATION

下丘脑-垂体-肾上腺皮质轴在脑缺血中的作用 过渡到子宫外生活是众所周知的。 这条轴线也可能 对发育中的大脑产生调节作用。 最近 有证据表明，产前皮质类固醇（类固醇）治疗胎儿 成熟降低了脑室内出血的发生率。 因此，在本发明中， 该轴在大脑成熟中很可能是重要的。 然而，尽管如此， 产前类固醇对发育中的大脑的影响并不好 记录在案。 这项建议审查了产前检查的假设， 类固醇使大脑生理成熟并改善病理生理 发展 生理学、组织学、生物化学和分子生物学 方法结合在以下具体目标：目标1检查 产前激素对血脑屏障功能的影响 胎儿和新生羔羊。 BBB渗透性通过 14 C-α-氨基异丁酸集成技术。的假设 产前类固醇能加速血液的成熟 脑屏障 目的2检查类固醇预处理对 胎羊、新生羊和成年羊的脑容量调节。 大脑 通过标准方法测量体积、水和电解质， 用甘露醇实现分级渗透应力。 假设是 试验表明，类固醇预处理可改善脑容量调节， 胎儿和新生儿。 目标3检查类固醇的效果 预处理对Na ~+，K ~+-ATP酶活性和特异性同工酶基因的影响 在脑和脉络丛中表达。我们还将研究 这些增加与类固醇的成熟效应直接相关 脑容量调节的研究 目标4a考察了 产前类固醇对脑缺血的神经保护作用 胎儿 在产前类固醇或安慰剂后， 椎枕动脉结扎后双侧颈动脉闭塞 是的测量胎儿脑灌注和代谢 在缺血40分钟之前、之后，以及在缺血48小时期间， 再灌注 脑脊液损伤标志物、脑脂质 过氧化产物，组织学和免疫组织化学将确定 脑损伤及脑水、电解质组织水肿。 有待验证的假设是，产前类固醇会削弱大脑 对胎儿的伤害。 目的4 b检查产前类固醇对 缺血和正常脑组织Na ~+，K ~+-ATP酶活性及基因表达 大脑，如目标3。 有待检验的假设是， 类固醇减轻缺血相关Na+，K+-ATP酶降低 活性和基因表达。拟议的研究将提供 关于产前类固醇对生理功能影响的重要信息 以及病理生理性脑血管和脑成熟。

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.