The Ventral Medulla and the Sudden Infant Death Syndrome

描述（由申请人提供）：尽管1992年国家推荐仰卧睡姿后，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。其总发病率为千分之0.6。基于该项目的第一个周期，我们假设SIDS病例的神经学亚群是由于髓质5-羟色胺系统的发育异常，这些异常干扰了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，如缺氧、高碳血症、窒息、热应激、血压变化和/或反射性呼吸暂停。所谓“髓质5-HT系统”，我们指的是位于中缝和中缝外网状结构和髓质腹侧面的一组相互关联的5-HT和非5-HT神经元，它们影响体内平衡功能，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。提出的第二个周期的总体目标是深入定义髓质5-羟色胺系统的组织、功能和发展，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Project 1中，我们将分析人类生命早期髓质5-HT系统的神经化学组织，并进一步表征其在SIDS病例中的病理特征。在项目2中，我们将定义仔猪髓质5-羟色胺系统的神经化学组织，这是人类婴儿体内平衡生理学的一个模型，我们将研究其中特定神经元破坏对仔猪中枢化学敏感性、呼吸和上呼吸道控制的影响。在项目3中，我们将研究髓质5-羟色胺系统中断对仔猪睡眠、热应激反应和心肺稳定性的影响。在Project 4中，我们将研究大鼠脑干还原制备中髓质5-HT系统在神经发生、呼吸暂停和喘气中的作用。在项目5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，我们将使用命运定位工具在基因工程小鼠中研究髓质5-羟色胺系统的产前发育。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）会改变髓质5-羟色胺系统的产前发育，增加出生后小岛屿发展中国家的风险这一必然假设的各个方面。这六个项目将由三个核心单元提供服务：行政核心(A)，解剖学核心(B)和整个动物生理学核心(C)。拟议的研究应该为髓质5-羟色胺系统在体内平衡控制和婴儿猝死中的作用提供重要的见解，这将是设计特定干预措施的关键(例如，

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.