The Ventral Medulla and the Sudden Infant Death Syndrome

描述（由申请人提供）：尽管在1992年国家推荐仰卧位睡眠后，婴儿猝死综合征（SIDS）的发病率下降了近50%，但SIDS仍然是美国新生儿后期婴儿死亡的主要原因。其总发病率为0.6/1000活产。基于该项目的第一个周期，我们假设SIDS病例的神经亚组是由于髓质5-HT系统的发育异常，这些异常干扰了对婴儿睡眠期间可能危及生命但经常发生的事件的保护性稳态反应，例如缺氧，高碳酸血症，窒息，热应激，血压变化和/或反射性呼吸暂停。“延髓5-HT系统”是指在中缝和中缝外网状结构和延髓腹侧表面中的一组相互关联的5-HT和非5-HT神经元，其影响稳态功能，即，呼吸、对二氧化碳和氧气的化学敏感性、上呼吸道反射、血压控制、心率、体温调节和睡眠。拟议的第二周期的总体目标是深入定义骨髓5-HT系统的组织、功能和发育、其功能障碍导致猝死的机制以及这种功能障碍的潜在原因。在项目1中，我们将分析人类早期延髓5-HT系统的神经化学组织，并进一步描述SIDS病例的病理学特征。在项目2中，我们将定义在小猪，人类婴儿稳态生理学模型的髓质5-HT系统的neurochemieal organization，我们将检查特定的神经元中断内的影响，对中央化疗敏感性，呼吸，和上呼吸道控制的小猪。在项目3中，我们将研究在睡眠，热应激反应和心肺稳定性的影响，在延髓5-HT系统中断的仔猪。在项目4中，我们将研究延髓5-HT系统在大鼠脑干简化制备中的神经发生、呼吸正常和喘息中的作用。在项目五中，我们将研究化学敏感性的细胞机制及其在体外培养的髓质5-HT神经元的发育。在项目6中，我们将在基因工程小鼠中使用命运绘图工具检查髓质5-HT系统的产前发育。在项目1、4、5和6中，我们将研究暴露于尼古丁（香烟烟雾的主要有毒成分）改变骨髓5-HT系统的产前发育，增加出生后SIDS风险的推论假设的各个方面。这六个项目将由三个核心单元提供服务：行政核心（A），解剖核心（B）和整体动物生理学核心（C）。拟议的研究应提供有关延髓5-HT系统在稳态控制和婴儿猝死中的作用的重要见解，这对设计特定干预措施（例如， 药物），以预防或改善受影响的SIDS婴儿的髓质5-HT功能障碍。

DESCRIPTION (provided by applicant): Despite an almost 50% decline in the incidence of the sudden infant death syndrome (SIDS) following the 1992 national recommendation for the supine sleep position, SIDS remains the leading cause of postneonatal infant mortality in the United States. Its overall incidence is 0.6/1000 live births. Based upon the program project's first cycle, we hypothesize that a neurological subset of SIDS cases is due to developmental abnormalities in the medullary 5-HT system that interfere with protective homeostatic responses to potentially life-threatening, but often occurring, events during infant sleep, such as hypoxia, hypercarbia, asphyxia, thermal stresses, blood pressure changes, and/or reflex apnea. By "medullary 5-HT system", we mean an inter-related group of 5-HT and non-5-HT neurons in the raphe' and extra-raphe' reticular formation and ventral surface of the medulla that influence homeostatic functions, i.e., respiration, chemosensitivity to carbon dioxide and oxygen, upper airway reflexes, blood pressure control, heart rate, thermoregulation, and sleep. The overall goal of the proposed second cycle is to define in-depth the organization, function, and development of the medullary 5-HT system, the mechanism(s) by which its dysfunction results in sudden death, and potential causes of this dysfunction. In Project 1, we will analyze the neurochemical organization of the medullary 5-HT system in early human life, and we will further characterize its pathology in SIDS cases. In Project 2, we will define the neurochemieal organization of the medullary 5-HT system in the piglet, a model of human infant homeostatic physiology, and we will examine the effects of specific neuronal disruptions within it on central chemosensitivity, respiration, and upper airway control in the piglet. In Project 3, we will examine the effects of disruptions in the medullary 5-HT system upon sleep, thermal stress responses, and cardiorespiratory stability in the piglet. In Project 4, we will study the rote of the medullary 5-HT system in neurogenesis, eupnea, and gasping in the reduced preparation of the rat brainstem. In Project 5, we will study cellular mechanisms underlying Chemosensitivity and their development medullary 5-HT neurons in vitro. In Project 6, we will examine the prenatal development of the medullary 5-HT system with fate mapping tools in genetically engineered mice. In Projects 1, 4, 5, and 6, we will examine aspects of the corollary hypothesis that exposure to nicotine (a major toxic component of cigarette smoke) alters the prenatal development of the medullary 5-HT system, increasing the postnatal risk for SIDS. The six projects will be served by three core units: an Administrative Core (A), an Anatomy Core (B) and a Whole Animal Physiology Core (C). The proposed studies should provide important insights into the role of the medullary 5-HT system in homeostatic control and in sudden infant death that will be critical in the design of specific interventions (e.g., drugs) to prevent or ameliorate medullary 5-HT dysfunction in affected SIDS infants.