THE MEDULLARY SEROTONERGIC SYSTEM IN SIDS BRAINSTEMS

小岛屿发展中国家脑干的髓质血清素系统

• 批准号: 7410019
• 负责人: HANNAH C KINNEY
• 金额: $ 26.79万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7410019
• 关键词: 3-Dimensional; Affect; Affinity; Age; Animal Model; Autoradiography; Binding; Brain Stem; Cells; Citalopram; Computer Assisted; Computers; Data; Defect; Development; Embryo; Epidemiologic Studies; Functional disorder; Genetic; Goals; Grant; Hormone Receptor; Hormones; Human; In Situ; In Situ Hybridization; Infant; Label; Lead; Link; Localized; Maps; Measures; Messenger RNA; Methods; Nature; Neuroanatomy; Neuromodulator; Neurons; Neuropeptides; Nicotine; Nicotinic Receptors; Numbers; Pathology; Pathway interactions; Pattern; Pregnancy; Range; Reflex action; Regulation; Relative (related person); Research; Risk; Secondary to; Serotonin; Site; Structure of nucleus infundibularis hypothalami; Substance P; Sudden infant death syndrome; Surface; Synapses; System; Testing; Thinking; Time; Tissues; Transcript; base; density; embryo/fetus; fetal; immunocytochemistry; infancy; interest; maternal cigarette smoking; medullary serotonergic system; neurochemistry; neurotransmission; novel; postnatal; prenatal influence; prevent; radioligand; receptor; receptor binding; serotonin receptor; serotonin transporter

Project 1 builds upon a key observation made in SIDS brainstems in the last grant cycle that serotonergic (5-HT) receptor binding is abnormal in regions of the medulla that contain 5-HT neurons and that are thought to be critical in the modulation of state-dependent, homeostatic reflexes. For the next cycle, we propose that these 5-HT receptor binding abnormalities are not necessarily the primary and/or only defect in 5-HT neurotransmission in these cases. Rather, they may represent a marker of primary and/or other defects elsewhere in 5-HT neurons, e.g., in the expression of the serotonin transporter (SERT), and/or in the neuropeptides substance P (SP) and/or thyrotrophin releasing hormone (TRH) that are known to colocalize with 5-HT and are its key neuromodulators. The proposed studies are novel in that they involve an indepth characterization of the neurochemical organization of the medullary 5-HT system in infancy, the peak age range of SIDS, and of its pathology in SIDS infants. We are especially interested in nicotinic receptor-related neuroanatomy in the medullary- 5-HT system in human gestation due to epidemiologic studies that link maternal cigarette smoking during pregnancy and increased risk for SIDS, and our finding of an association between maternal cigarette smoking during pregnancy and lowered 5-HT receptor binding in the arcuate nucleus, a ventral surface component of the medullary 5-HT system. In Specific Aim 1, we will determine the profile of SERT expression in the human brainstem across early development. In Specific Aim 2, we will determine the brainstem expression of SERT in SIDS cases compared to controls. In Specific Aim 3, we will determine the neurochemical organization of the medullary 5-HT system in the human infant relative to the inter-relationships of 5-HT neurons with SP and TRH. In Specific Aim 4, we will determine the developmental profile of receptor binding to SP and TRH in the medullary 5-HT system in SIDS cases compared to age-matched controls. In Specific Aim 5, we will determine the neuroanatomic inter-relationships between nicotinic receptors and 5-HT neurons in the human medulla during gestation. These studies will utilize tissue receptor autoradiography, single- and double-labeling immunocymchemistry, and in situ hybridization to mRNA transcripts with 2- and 3-dimensional, computer-based graphics and quantitation in alternate tissue sections from the same cases. Further characterization of abnormalities in the medullary 5-HT system in SIDS cases should help lead to the development of strategies to clinically identify and prevent them in affected infants, the ultimate goal of this research.

项目1基于在上一个赠款周期中在SIDS脑干​​中进行的关键观察，即在含有5-HT神经元的延髓的血清素能（5-HT）受体结合在延髓异常，并且被认为在调节状态依赖性的，稳态反射中至关重要。在下一个周期中，我们建议在这些情况下，这些5-HT受体结合异常不一定是5-HT神经传递中的原发性和/或缺陷。相反，它们可能代表5-HT神经元中其他位置的主要和/或其他缺陷的标志物，例如，在5-羟色胺转运蛋白转运蛋白（SERT）和/或神经肽物质P（SP）和/或甲状腺营养性激素（TRH）中，已知可与5-HT和5-HT和甲状腺相关的Neurromod的神经肽P（sp）和/或甲状腺营养蛋白释放激素（TRH）中。拟议的研究是新颖的，因为它们涉及一个深入 髓质5-HT系统的神经化学组织在婴儿期，SIDS的峰值年龄范围及其在SIDS婴儿中的病理学表征。由于流行病学研究，我们对人妊娠系统中与烟碱受体相关的神经解剖学特别感兴趣，这些研究将孕妇在怀孕期间吸烟与SIDS的风险增加以及我们在怀孕期间吸烟和5-HT受体在5-HT表面降低的甲型构成核心的结合的孕产妇吸烟之间的关联。 在特定的目标1中，我们将在早期发展中确定人类脑干中SERT表达的特征。在特定的目标2中，我们将确定与对照组相比，在SIDS病例中SERT的脑干表达。在特定目标3中，我们将根据5-HT神经元与SP和TRH的相互关系来确定人类婴儿中髓质5-HT系统的神经化学组织。在特定的目标4中，与年龄匹配的对照相比，我们将确定在SIDS病例中髓质5-HT系统中受体与SP和TRH结合的发育曲线。在特定目标5中，我们将在妊娠期间确定烟碱受体和5-HT神经元之间的神经解剖学相互关系。这些研究将利用组织受体放射自显影，单标记免疫化学，以及与同一病例中替代组织中的2和3二维的基于计算机的图形和定量的原位杂交与mRNA转录本的原位杂交。在SIDS病例中，在髓质5-HT系统中的异常进一步表征应有助于发展策略以临床识别和预防受影响的婴儿，这是这项研究的最终目标。