NEUROCHEMICAL PATHOLOGY IN SIDS BRAINSTEMS

项目1在上一个周期的主要发现是， SIDS与5-HT系统有关。我们现在设想小岛屿发展中国家是一个复杂的， 一种异质性过程，除了5-HT，还涉及多种递质，多种应激源起作用， 同时，多种遗传和环境因素，包括慢性缺氧和男性 性别，增加脑干缺陷。我们的具体目标是：1）确定神经化学物质 SIDS患者延髓中γ-氨基丁酸（GABA）的解剖。我们将确定 GABA神经元密度、与GABA共定位的5-HT神经元百分比、GABAA受体 SIDS病例与对照组GABAA受体亚单位的结合和细胞定位 根据年龄调整。2)为了确定SP表达神经元和NK 1的神经化学解剖， 在SIDS病例中髓质中的受体。我们将确定SP神经元的数量和密度， SIDS病例中共定位SP、SP结合和NK 1细胞定位的5-HT神经元百分比 与年龄调整后的对照组相比。我们还将确定是否有5-HT 1A和假定的SIDS病例 GABAA受体结合异常与SP结合异常相同。3)到 确定雌激素和睾酮在SIDS髓质病理中的作用。我们将测试 假设：在SIDS病例（男性和女性）中， 5-HT系统和/或其投射部位与年龄校正的对照组相比;高血清睾酮 在相同的SIDS病例中，血清睾酮水平与高雄激素结合相关; 与血清睾酮水平低的SIDS婴儿相比，睾酮水平较低的5-HT 1A受体结合 水平和控制。4)为了确定慢性间歇性缺氧在延髓 SIDS的病理学以及由于5-HT介导的 可塑性我们将检验这一假设，即SIDS病例显示出低缺氧反应， 舌下神经核与缺氧病例相比，反映在缺氧标志物减少，例如， 促红细胞生成素这一假设是基于这样的想法，即缺氧病例具有“正常”的能力， 而婴儿猝死综合征患者的这种能力受损。然后我们将检验这个假设 5-HT介导的对间歇性缺氧的可塑性的标志物（BDNF，TrkB受体）在 SIDS病例与舌下神经核缺氧病例相比。这一发现表明， 的SIDS婴儿适应间歇性缺氧由于5-HT中缝相关的异常和受损 长期便利化。这项研究是建立在一个复杂的脑干的新图像上的 表型的SIDS基于一个独特的数据库积累超过20年，在我们的实验室。

The major discovery of Project 1 in the last cycle was that multiple abnormalities in the medullary serotonergic (5-HT) system are associated with SIDS. We now envision SIDS as a complex and heterogeneous process which involves multiple transmitters in addition to 5-HT, multiple stressors acting simultaneously, and multiple genetic and environmental factors, including chronic hypoxia and male gender, augmenting the brainstem defects. Our Specific Aims are: 1) To determine the neurochemical anatomy of Y-aminobutyric acid (GABA) in the medulla in SIDS cases. We will determine the number and density of GABA neurons, percent of 5-HT neurons that co-localize with GABA, GABAA receptor binding, and cellular localization of GABAA receptor subunits in SIDS cases compared with controls adjusted for age. 2) To determine the neurochemical anatomy of SP-expressing neurons and NK1 receptors in the medulla in SIDS cases. We will determine the number and density of SP neurons, the percent of 5-HT neurons that co-localize SP, SP binding, and cellular localization of NK1 in SIDS cases compared to controls adjusted for age. We will also determine if the SIDS cases with 5-HT1A and putative GABAA receptor binding abnormalities are the same as those with SP binding abnormalities. 3) To determine the role of estrogen and testosterone in the medullary pathology of SIDS. We will test the hypotheses that: androgen receptor binding is elevated in SIDS cases (male and female) in the medullary 5-HT system and/or its projection sites compared to controls adjusted for age; high serum testosterone levels correlate with high androgen binding in the same SIDS cases; and male SIDS cases with high serum testosterone levels have lower 5-HT1A receptor binding than SIDS infants with low serum testosterone levels and controls. 4) To determine the role of chronic intermittent hypoxia in the medullary pathology in SIDS and the role of compromised responses to hypoxia due to a defect in 5-HTmediated plasticity. We will test the hypothesis that SIDS cases show a reduced hypoxic response in the hypoglossal nucleus compared to hypoxic cases, as reflected in reduced hypoxic markers, e.g., erythropoietin. This hypothesis is based on the idea that hypoxic cases are equipped with a "normal" ability to respond to hypoxia, whereas the SIDS cases have an impaired ability. We will then test the hypothesis that markers of 5-HT-mediated plasticity to intermittent hypoxia (BDNF, TrkB receptors) are reduced in SIDS cases compared to hypoxic cases in the hypoglossal nucleus. This finding would suggest an inability of the SIDS infants to adapt to intermittent hypoxia due to 5-HT raphe-related abnormalities and impaired long-term facilitation. The proposed studies build upon an emerging picture of a complex brainstem phenotype in SIDS based upon a unique database accrued over 20 years in our laboratory.