The Ventral Medulla and the Sudden Infant Death Syndrome

尽管回归睡眠运动取得了成功，但婴儿猝死综合症(SIDS)仍然是当今美国新生儿后死亡的主要原因。该计划项目在上一个周期的主要发现是，延髓5-羟色胺(5-HT)系统的多种发育异常与小岛屿发展中国家有关。这些人类在项目1中的发现已经导致在项目2-4中，延髓5-羟色胺系统在动物模型中多种稳态功能的状态相关调节中发挥关键作用。此外，在项目5中，这些发现在脑干5-羟色胺系统的分子水平上建立了发育概况。这些发现导致了关于拟议的第三周期的以下压倒一切的假说：SID的一个重要子集是由于延髓5-羟色胺系统和相关神经调节系统的发育障碍，这些系统在产前发生，但在出生后的前6个月发挥其作用，在新生儿过渡到宫外生命的过程中，经历了维持独立动态平衡的回路的成熟，是SIDS的最大风险。 这种疾病损害了对可能威胁生命的、但在婴儿睡眠期间经常发生的应激源的保护性稳态反应，这些应激源反过来会导致体内平衡失调(缺氧、高碳酸血症)，每种疾病本身都可能不致命，但它们结合在一起会导致死亡。我们的目标是：1)明确多种递质/调节剂在小儿麻痹症婴儿神经化学髓质病理中的作用； 2)在啮齿动物模型中确定动态平衡应激源单独和联合作用对不同睡眠状态、不同性别和不同年龄的自主神经和呼吸功能的影响；3)确定慢性间歇性低氧在增强SIDs脑干病变中的作用；4)确定γ-氨基丁酸(GABA)、增食欲素、P物质、去甲肾上腺素和乙酰胆碱在动物模型中与延髓5-羟色胺系统相互作用中的作用；5)建立延髓5-羟色胺系统的组织和连接，它是由多个效应神经元介导的多种动态平衡功能的“积分器”；6)抑制(“沉默”)分子定义的5-羟色胺和GABA神经元亚群，并确定其在活着的小鼠中的生理后果。在提议的第三个周期中，我们将利用多学科方法测试超越假设，其中人、动物、组织切片、细胞培养和发育数据被整合在一起，从而相互告知和扩展以建立发病机制。 从蜂窝到系统级别的小岛屿发展中国家。

Despite the success of the Back-to-Sleep campaign, the sudden infant death syndrome (SIDS) remains the leading cause of postneonatal infant mortality in the United States today. The major discovery of this program project in the last cycle was that multiple developmental abnormalities in the medullary serotonergic (5-HT) system are associated with SIDS. These human findings in Project 1 have lead to the establishment of a critical role for the medullary 5-HT system in the state-related regulation of multiple homeostatic functions in animal models in Projects 2-4. Additionally, they have lead to establishment of the developmental profile at the molecular level of the brainstem 5-HT system in Project 5. These discoveries have lead to the following over-riding hypothesis for the proposed third cycle: an important subset of SIDS is due to a developmental disorder of the medullary 5-HT system and related neuromodulator systems that are incurred prenatally, but which exerts its effects postnatally¿ during the first 6 months of life when the newborn, in transitioning to extrauterine life, undergoes maturation of circuitry for maintaining independent homeostasis and is at the greatest risk for SIDS. This disorder impairs protective homeostatic responses to potentially life-threatening, but often occurring, stressors during infant sleep that lead in turn to homeostatic derangements (hypoxia, hypercarbia), each potentially non-lethal in themselves, but which in combination precipitate death. Our objectives are: 1) To define the role of multiple transmitters/modulators in the neurochemical medullary pathology in SIDS infants; 2) To determine in rodent models the effect of homeostatic stressors¿alone and in combination¿upon autonomic and respiratory function during different sleep states, in males and females, and at different ages; 3) To determine the role of chronic intermittent hypoxia in the potentiation of the brainstem pathology in SIDS; 4) To determine the role of y-aminobutyric acid (GABA), orexin, substance P, norepinephrine, and acetylcholine in interacting with the medullary 5-HT system in homeostatic regulation in animal models; 5) To establish the organization and connectivity of the medullary 5-HT system¿the "integrator" of diverse homeostatic functions mediated by multiple effector neurons; 6) To inhibit ("silence") molecularly defined subsets of 5-HT and GABA neurons and determine the physiological consequences in the living mouse. In the proposed third cycle, we will test the over-riding hypothesis utilizing a multidisciplinary approach in which human, animal, tissue slice, cell culture, and developmental data are integrated together, thereby informing and expanding upon each other towards establishing the pathogenesis of SIDS from the cellular to systems level.