THE MEDULLARY SEROTONERGIC SYSTEM IN SIDS BRAINSTEMS

项目1建立在上一个资助周期对小岛屿发展中国家脑干的关键观察基础上，即5-羟色胺能（5-HT）受体结合在含有5-HT神经元的髓质区域异常，这些神经元被认为是调节状态依赖性、稳态反射的关键。对于下一个周期，我们提出这些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，它们可能代表了5-HT神经元其他部位的原发性和/或其他缺陷的标志，例如，5-羟色胺转运体（SERT）的表达，和/或神经肽P物质（SP）和/或促甲状腺激素释放激素（TRH）的表达，这些物质已知与5-羟色胺共定位，是其关键的神经调节剂。提出的研究是新颖的，因为它们涉及一个深度

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.