HORMONAL REGULATION OF BRAIN MATURATION

下丘脑-垂体-肾上腺皮质轴在脑出血中的重要性 过渡到宫外生活是众所周知的。这个轴线也有可能 对发育中的大脑施加调节影响。近期 有证据表明，产前皮质类固醇(类固醇)治疗胎儿 成熟可降低脑室出血的发生率。因此， 这个轴很可能对大脑的成熟很重要。不过， 产前类固醇对发育中的大脑的影响一直不是很好。 有记录在案。这项建议检验了产前的假设 类固醇调节生理和改善病理生理脑功能 发展。生理学、组氨酸、生化和分子 这些方法结合在以下具体目标中：目标1检查 产前激素对血脑屏障功能的影响 在胎儿和新生羔羊中。血脑屏障通透性由 14C-α-氨基异丁酸的合成技术假说 需要测试的是，产前类固醇会加速血液的成熟- 大脑屏障。目的2研究类固醇预处理对血管紧张素转换酶的影响。 胚胎、新生和成年绵羊的脑容量调节。脑区 体积，水和电解质，用标准方法和 用甘露醇实现的分级渗透胁迫。假设是 试验表明，类固醇预处理改善了脑容量调节 胎儿和新生儿。目标3检查类固醇的作用 预处理对Na~+，K~+-ATPase活性和特异性异构体基因的影响 在脑和脉络丛中的表达。我们还将研究是否 这些增加与类固醇的成熟效应直接相关。 关于大脑容量的调节。目标4a考察了潜在的 孕期激素对大鼠脑缺血的神经保护作用 胎儿。在产前服用类固醇或安慰剂后，脑缺血是由 椎枕部结扎术后双侧颈动脉闭塞 吻合术。测量胎儿脑血流灌注和代谢。 在缺血前、缺血40分钟后和在48小时内顺序 再灌流。脑脊液损伤标志物、脑脂 过氧化产物、组织学和免疫组织化学将定义 脑损伤，脑组织积水和电解性组织水肿。 需要检验的假设是，产前类固醇会削弱大脑 胎儿受伤。目的4b研究产前使用类固醇对 脑缺血与正常组织Na+，K+-ATPase活性及基因表达 大脑，如目标3。需要检验的假设是产前 类固醇减轻缺血引起的Na~+，K~+-ATPase降低 活性和基因表达。拟议的研究将提供 产前类固醇对生理学影响的重要信息 以及病理生理学、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.