The Hippocampus and Brainstem in the Sudden Infant Death Syndrome

项目摘要 尽管开展了安全睡眠运动，但小岛屿发展中国家仍是2010年新生儿后期婴儿死亡的主要原因。 今天的美国，总比率为0.40/1000活产。我们的实验室提供了令人信服的 在4个独立的数据集中，有证据表明髓质（下丘脑）中的多巴胺能（5-HT）网络存在缺陷。 脑干）参与睡眠期间对危及生命的挑战的保护性反应。这些5-HT缺陷 包括与年龄调整的对照组相比，SIDS病例中5-HT本身的水平显著降低（约26%）。 在过去的二十年里，我们的团队已经提供了大量的证据，从使用神经化学物质的研究中， 冷冻组织中的技术，SIDS的一个子集的特征是多巴胺能（5-HT）脑干病理学 在涉及心肺控制和唤醒的区域。2015年，我们报道了一种新的解剖学方法， 在光学显微镜研究中发现，在海马的齿状回（DG）中有一个主要的亚群， SIDS病例（约40%）在单独的数据集中。在后一个数据集中，5-HT脑干神经化学缺陷可能 由于海马组织来自福尔马林固定的脑组织， 圣地亚哥法医系统的一部分小岛屿发展中国家的齿状异常是 颗粒细胞分散（GCD），其显著特征在于颗粒细胞（GC）的双层化， 即所谓的齿状双胺化（DB）。在SIDS病例中，DB和相关GC异常几乎 以前只在颞叶癫痫（TLE）患者中报道过，其中一些人死于 癫痫猝死（SUDEP）我们现在要问：1）SIDS-DB病例是否也有5-HT 脑干病理学2)SIDS-DB和5-HT病理学的联合实体是否共享分子， TLE和/或SUDEP的细胞和遗传特征？3)SIDS-DB和5-HT病理是否代表 一系列潜在的、内在的颞叶脆弱性中的一个， 突然死亡的关系吗在这些情况下，DB被假定为一种发育异常， GC增殖和/或迁移，以及TLE中阿蒙角硬化的前驱病变。我们将测试 总的假设是DG和髓质5-HT网络在相同的SIDS病例中均异常， 同时，SIDS合并DB的病例与TLE具有共同的分子、细胞和遗传特征 和/或SUDEP。在四个具体目标中，我们将使用各种最先进的技术来测试这一假设， 包括用激光捕获显微切割在海马颗粒细胞中的转录组学， SIDS伴DB病例的外显子组测序。这项研究的潜在影响是发现了 小岛屿发展中国家的大亚组（40%），这将导致干预战略，以及生物标志物，以确定 有生命危险的婴儿了解小岛屿发展中国家的DB也开辟了途径，阐明细胞和 婴儿期后不明原因猝死的分子病理学，包括SUDC和SUDEP。

Project Summary Despite the safe sleep campaign, SIDS remains the leading cause of postneonatal infant mortality in the United States today, with an overall rate of 0.40/1000 live births. Our laboratory has provided compelling evidence in 4 independent datasets of defects in the serotonergic (5-HT) network in the medulla (lower brainstem) involved in protective responses to life-threatening challenges during sleep. These 5-HT defects include significantly decreased levels (~26%) of 5-HT itself in SIDS cases compared to age-adjusted controls. Over the last two decades, our group has provided substantial evidence, from studies using neurochemical techniques in frozen tissue, that a subset of SIDS is characterized by serotonergic (5-HT) brainstem pathology in regions involved in cardiorespiratory control and arousal. In 2015, we then reported a novel anatomic finding, from light microscope studies, in the dentate gyrus (DG) of the hippocampus in a major subgroup of SIDS cases (~40%) in a separate dataset. In this latter dataset, 5-HT brainstem neurochemical defects could not be simultaneously sought because the hippocampal tissues were from formalin fixed brains in the archives of the San Diego medical examiner's system. The dentate abnormality in SIDS is part of the spectrum of granule cell dispersion (GCD), which is characterized prominently by bilamination of the granule cells (GCs), so-called dentate bilamination (DB). DB and associated GC abnormalities in the SIDS cases had almost exclusively been reported previously in patients with temporal lobe epilepsy (TLE), some of who died from sudden unexplained death in epilepsy (SUDEP). We now ask: 1) Do cases of SIDS-DB also have 5-HT brainstem pathology? 2) Does the combined entity of SIDS-DB and 5-HT pathology share molecular, cellular, and genetic features with TLE and/or SUDEP? 3) Does SIDS-DB and 5-HT pathology represent one of many entities on a spectrum of underlying, intrinsic temporal lobe vulnerabilities associated with sudden death across life? In these scenarios, DB is postulated to be a developmental abnormality in GC proliferation and/or migration, and a precursor lesion to Ammon's horn sclerosis in TLE. We will test the overall hypothesis that the DG and medullary 5-HT network are both abnormal in the same SIDS cases, and that SIDS cases with DB share molecular, cellular, and genetic features in common with TLE and/or SUDEP. In four Specific Aims, we will test this hypothesis using a variety of state-of-the-art techniques, including transcriptomics with laser capture microdissection in the granule cells of the hippocampus, and whole exome sequencing in SIDS cases with DB. The study's potential impact is the discovery of a cause(s) of large subgroup (40%) of SIDS that will lead to intervention strategies, as well as biomarkers to identify living infants at risk. Understanding DB in SIDS also opens up avenues to elucidate the cellular and molecular pathology of sudden unexplained death beyond infancy, including SUDC and SUDEP.