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 建立在上一个资助周期中在 SIDS 脑干中进行的一项关键观察的基础上，即在含有 5-HT 神经元的髓质区域中，血清素能 (5-HT) 受体结合异常，并且这些区域被认为对于状态依赖性稳态反射的调节至关重要。对于下一个周期，我们建议这些 5-HT 受体结合异常不一定是这些病例中 5-HT 神经传递的主要和/或唯一缺陷。相反，它们可能代表 5-HT 神经元中其他部位的原发性和/或其他缺陷的标记，例如，血清素转运蛋白 (SERT) 的表达，和/或已知与 5-HT 共定位且是其关键神经调节剂的神经肽 P 物质 (SP) 和/或促甲状腺激素释放激素 (TRH) 中的缺陷。拟议的研究是新颖的，因为它们涉及深入的 婴儿期髓质 5-HT 系统的神经化学组织特征、SIDS 的峰值年龄范围及其 SIDS 婴儿的病理学。我们对人类妊娠期髓质 5-HT 系统中与烟碱受体相关的神经解剖学特别感兴趣，因为流行病学研究表明母亲在怀孕期间吸烟与 SIDS 风险增加有关，并且我们发现母亲在怀孕期间吸烟与弓状核（髓质 5-HT 系统的腹侧表面成分）中 5-HT 受体结合降低之间存在关联。 在具体目标 1 中，我们将确定早期发育过程中人类脑干中 SERT 表达的概况。在具体目标 2 中，我们将确定 SIDS 病例与对照组相比的 SERT 脑干表达。在具体目标 3 中，我们将确定人类婴儿髓质 5-HT 系统的神经化学组织，以及 5-HT 神经元与 SP 和 TRH 的相互关系。在具体目标 4 中，我们将确定 SIDS 病例中与年龄匹配的对照相比，与髓质 5-HT 系统中 SP 和 TRH 结合的受体的发育概况。在具体目标 5 中，我们将确定妊娠期间人类髓质中烟碱受体和 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、单标记和双标记免疫细胞化学，以及利用 2 维和 3 维、基于计算机的图形对 mRNA 转录物进行原位杂交，并对同一病例的替代组织切片进行定量。对 SIDS 病例中髓质 5-HT 系统异常的进一步表征应有助于制定临床识别和预防受影响婴儿的策略，这也是本研究的最终目标。