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建立在上一次授予周期中在小岛屿发展中国家脑部所做的一项关键观察的基础上，即5-羟色胺(5-HT)受体结合在含有5-羟色胺神经元的延髓区域中异常，这些区域被认为在调节状态依赖的、内环境平衡的反射中起关键作用。对于下一个周期，我们认为这些5-羟色胺受体结合异常不一定是这些病例中5-羟色胺神经传递的主要和/或唯一缺陷。相反，它们可能代表着5-羟色胺神经元其他部位原发和/或其他缺陷的标志，例如，在5-羟色胺转运体(SERT)的表达中，和/或在神经肽P物质(SP)和/或促甲状腺激素释放激素(TRH)中，已知它们与5-羟色胺共存，是其关键的神经调节剂。拟议的研究是新颖的，因为它们涉及一种深入的 婴儿时期延髓5-羟色胺系统的神经化学组织的特征，小岛屿发展中国家的高峰年龄范围，以及小岛屿发展中国家婴儿的病理学。我们对人类妊娠延髓-5-羟色胺系统中与尼古丁受体相关的神经解剖学特别感兴趣，因为流行病学研究将孕期吸烟与SDS风险增加联系起来，以及我们发现孕期吸烟与弓状核中5-羟色胺受体结合降低之间的关联，弓状核是延髓5-羟色胺系统的腹面成分。在特定的目标1中，我们将确定SERT在人类脑干发育早期的表达谱。在特定的目标2中，我们将与对照组相比，测定SIDS患者脑干中SERT的表达。在具体目标3中，我们将确定人类婴儿延髓5-羟色胺系统的神经化学组织与5-羟色胺神经元与SP和TRH的相互关系。在特定的目标4中，我们将确定与年龄匹配的对照组相比，小儿麻痹症患者延髓5-羟色胺系统中与SP和TRH结合的受体的发育情况。在具体目标5中，我们将确定妊娠期间人延髓中尼古丁受体和5-羟色胺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、单标记和双标记免疫细胞化学以及与来自相同病例的交替组织切片中的二维和三维、基于计算机的图形和定量的mRNA转录本的原位杂交。小儿麻痹症患者延髓5-羟色胺系统异常的进一步表征应有助于开发临床识别和预防受影响婴儿的策略，这是本研究的最终目标。