BRAINSTEM MATURATION IN THE SUDDEN INFANT DEATH SYNDROME

婴儿猝死综合征（SEDS）是新生儿后期婴儿死亡的主要原因， 发病率为0.8/1 000活产。其原因不明。根据我们对婴儿猝死综合症患者的脑干研究， 在最后一个格兰特周期中，我们提出了一个关于腹侧延髓作用的扩展假设，该区域与 化学感受、自主反应、呼吸驱动和体温调节，以及神经递质5-羟色胺（5- HT）在SIDS发病机制中的作用：SIDS或SIDS的一个子集，是由于腹侧发育异常引起的。 延髓网络组成的菱形唇源性，多巴胺能神经元，这种异常的结果是， 对危及生命的挑战的保护性反应失败（例如，窒息、缺氧、高碳酸血症） 在特定目的1-3中，我们将描述5-HT腹侧延髓网络的正常发育， 在生命早期的脑组织中，SIDS发病的时间段。我们将利用选定的标记物对5-HT 细胞、末端、受体亚型和合成酶色氨酸羟化酶，使用组织放射自显影术， 免疫细胞化学和原位杂交技术。我们将 然后确定与年龄匹配的对照组相比，SIDS受害者的5-HT发育是如何异常的。 5-HT标记物。在具体目标4中，我们将使用以下方法确定哪些细胞群来自人类菱形唇 细胞和分子标记的转录因子牵连在菱形唇衍生的动物研究，我们 将确定SIDS受害者腹侧髓质网络中受影响的核团是否来自同一个胚胎 原基我们将确定是否有一个异常数量的神经元和反应性星形胶质细胞（胶质细胞增生）， 菱形唇源性核我们预测，我们不会在这些细胞核中发现胶质增生（瘢痕）， 表明是发育性而非退化性缺陷拟议的研究应：证实5-HT缺陷 在腹侧髓质的SIDS受害者;提供洞察正常发展和分子和化学 解剖人类5-羟色胺腹侧延髓网络，并提出线索，异常功能的小岛屿发展中国家受害者， 在动物模型中进行测试，并在人类婴儿中设计特定的预防策略和诊断测试。

The sudden infant death syndrome (SEDS) is the leading cause of postneonatal infant mortality, with an overall incidence of 0.8/1000 live births. Its cause(s) is unknown. Based upon our brainstem studies in SIDS victims during the last grant cycle, we propose an expanded hypothesis concerning the role of the ventral medulla, a region related to chemoreception, autonomic responses, respiratory drive, and thermoregulation, and the neurotransmitter, serotonin (5- HT) in the pathogenesis of SIDS: SIDS, or a subset of SIDS, is due to a developmental abnormality in a ventral medullary network composed of rhombic lip-derived, serotonergic neurons, and this abnormality results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypoxia, hypercapnia) during sleep, hi Specific Aims 1-3, we will characterize the normal development of the 5-HT ventral medullary network in brain tissues across early life, the time-period of the pathogenesis of SIDS. We will utilize selected markers to 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue autoradiography, immunocytochemistry, and in situ hybridization in brain tissues from human embryos, fetuses, and infants. We will then determine how 5-HT development is abnormal in SIDS victims compared to age-matched controls with the same. 5-HT markers. In Specific Aim 4, we will establish which cell populations derive from the human rhombic lip using cellular and molecular markers to transcription factors implicated in rhombic lip-derivation in animal studies, and we will determine if the affected nuclei in the ventral medullary network in SIDS victims derive from this same embryonic anlage. We will determine if there is an abnormal number of neurons and reactive astrocytes (gliosis) in selected rhombic lip-derived nuclei in SIDS victims. We predict that we will not find gliosis (scarring) in these nuclei, suggesting a developmental, rather than degenerative, defect. Theproposed studies should: substantiate a 5-HT defect in the ventral medulla of SIDS victims; provide insight into the normal development and the molecular and chemical anatomy of the human 5-HT ventral medullary network; and suggest clues about abnormal function in SIDS victims for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants.