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该地区新生儿后死亡的主要原因。 今天的美国，总的活产儿比率为0.40/1000。我们的实验室提供了令人信服的 延髓5-羟色胺(5-羟色胺)网络缺陷的4个独立数据集的证据(下 脑干)参与对睡眠中威胁生命的挑战的保护性反应。这些5-羟色胺缺陷 与年龄调整的对照组相比，SIDS患者的5-羟色胺水平显著降低(~26%)。 在过去的二十年里，我们小组通过使用神经化学物质的研究提供了大量的证据。 冰冻组织中的技术，SID的一个亚组以5-羟色胺(5-HT)脑干病理为特征 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 从光学显微镜研究中发现，在海马齿状回(DG)中， 小岛屿发展中国家病例(约40%)在单独的数据集中。在后一个数据集中，5-羟色胺脑干神经化学缺陷可能 不是同时寻找的，因为海马体组织来自档案中固定了福尔马林的大脑 圣地亚哥验尸官的系统。小岛屿发展中国家的齿状异常是 颗粒细胞弥散(GCD)，其显著特征是颗粒细胞(GC)的双层化； 所谓的齿状双层化(DB)。小岛屿发展中国家的DB和相关GC异常几乎 先前在颞叶癫痫(TLE)患者中独家报道过，其中一些人死于 癫痫原因不明猝死(SUDEP)。我们现在问：1)SID-DB的病例是否也有5-羟色胺 脑干病理？2)SDS-DB和5-羟色胺病理的结合实体是否共享分子， TLE和/或SUDEP的细胞和遗传特征？3)SDS-DB和5-HT病理是否代表 与一系列潜在的、内在的颞叶漏洞相关的许多实体之一 伴随着生命中的突然死亡？在这些情况下，Db被假设为 GC增殖和/或迁移，以及TLE中阿蒙氏角硬化症的前驱病变。我们将测试 总体假设DG和延髓5-羟色胺网络在同一SID病例中均异常， 小儿麻痹症合并DB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验证这一假设， 包括用激光捕获显微切割技术在海马区颗粒细胞中进行转录切割，以及整个 小儿麻痹症合并DB患者的外显子组测序。这项研究的潜在影响是发现了一种病因(S) 将导致干预战略的小岛屿发展中国家的大亚群(40%)，以及识别生物标记物 活着的婴儿处于危险之中。了解小岛屿发展中国家中的DB也为阐明细胞和 婴儿期以上原因不明猝死的分子病理学，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.