THE MEDULLARY SEROTONERGIC SYSTEM: MECHANISMS OF AROUSAL FROM SLEEP

唤醒是婴儿在面临潜在威胁生命的缺氧时的一种重要保护机制 在睡眠期间，无论是由于呼吸道阻塞、重复呼吸、呼吸暂停或循环衰竭。我们的重点是 调节呼吸、脊髓运动活动和交感神经的下行或皮质下兴奋通路 控制体温、心率和血压的活动。我们现在知道70%的小岛屿发展中国家 婴儿5-HT1a受体和5-羟色胺转运体(5-HTT)结合减少，根据5-羟色胺表达 在调节觉醒的重要延髓区域，5-羟色胺神经元的数量增加， 运动、体温、心率和呼吸。延髓5-羟色胺神经元也接受兴奋性 食欲素能和抑制性GABA能输入本身在觉醒过程中起着重要作用。我们建议 由于延髓5-羟色胺(5-羟色胺)能(5-HT)功能异常导致 对于协调和有效的觉醒来说，下行通路的调节发生了变化，而死亡 由唤醒机制受损和外在应激源共同作用的结果 发育的关键阶段，通常是在睡眠期间。在分析有缺陷的唤醒机制时 对于小岛屿发展中国家来说，重要的是要考虑到许多小岛屿发展中国家的婴儿在 在死亡前几天或几周内。我们认为，反复暴露在亚临床缺氧环境中会导致觉醒 习惯化。习惯化是指一种对重复刺激的生理反应随着时间的推移而减弱 以防止对非危险或不重要的刺激作出不适当的反应 从睡眠中唤醒到危险的刺激，如严重的间歇性低氧可能会导致灾难性的后果 后果。在这个项目中，我们将定义大脑皮质下觉醒在发育过程中的特征。 并测试新的假设，即过度习惯是导致功能障碍的主要因素 唤醒。我们将进一步确定睡眠中有效唤醒对缺氧的反应是否受到影响 通过操纵5-HT1A和GABAA受体以及5-HTT，慢性间歇性接触 缺氧、过热和发烧，以及产前暴露在烟草烟雾中。我们对穷人的关注 了解皮质下觉醒的功能、病理生理学和神经解剖学，包括它与 温度调节，是这个项目的一大优势。这些研究的结果将提供关键信息 关于5-羟色胺在唤醒机制中的作用，并确定间歇性暴露之间的重要联系 低氧、5-羟色胺、觉醒和婴儿猝死综合征。这些信息将是至关重要的，并最终导致 了解小岛屿发展中国家的病理生理机制并开发治疗干预措施 根除所有小岛屿发展中国家的死亡。

Arousal is a vital protective mechanism in infants when confronted with potentially life-threatening hypoxia during sleep¿whether from airway obstruction, rebreathing, apnea, or circulatory failure. Our focus is on the descending, or subcortical, arousal pathways that modulate breathing, spinal motor activity, and sympathetic activity that controls body temperature, heart rate, and blood pressure. We now know that 70% of SIDS infants have decreased 5-HT1A receptor and serotonin transporter (5-HTT) binding, expressed per 5-HT neuron, and increased numbers of 5-HT neurons, in medullary regions important for modulating arousal, motor activity, body temperature, heart rate, and breathing. Medullary 5-HT neurons also receive excitatory orexinergic and inhibitory GABAergic inputs that by themselves have important roles in arousal. We propose that SIDS infants are at risk because of abnormalities in medullary serotonergic (5-HT) function that lead to altered modulation of descending pathways essential for coordinated and effective arousal, and that death results from a combination of impaired arousal mechanisms and extrinsic stressors that occurs during a critical stage of development and typically during sleep. In the analysis of defective arousal mechanisms in SIDS, it is important to consider that many SIDS infants have repeated episodes of apnea and hypoxia in the days or weeks prior to death. We propose that repeated exposure to subclinicai hypoxia leads to arousal habituation. Habituation refers to the waning over time of a physiological response to repetitive stimuli in order to prevent inappropriate responses to non-dangerous or non-important stimuli¿yet "habituation" of arousal from sleep to a dangerous stimulus such as severe intermittent hypoxia could lead to disastrous consequences. In this project, we will define the characteristics of subcortical arousals during development in the rat and test the novel hypothesis that excessive habituation is a major contributor to dysfunctional arousals. We will further determine whether effective arousal from sleep in response to hypoxia is affected by the manipulation of the 5-HT1A and GABAA receptor and the 5-HTT, chronic exposure to intermittent hypoxia, overheating and fever, and prenatal exposure to tobacco smoke. Our focus upon the poorly understood function, pathophysiology, and neuroanatomy of subcortical arousal, including its interaction with thermoregulation, is a major strength of this project. The results of these studies will provide key information about the role of serotonin in arousal mechanisms and identify important links between intermittent exposure to hypoxia, serotonin, arousal, and SIDS. This information will be critical and lead toward ultimately understanding the pathophysiological mechanisms of SIDS and developing therapeutic interventions to eradicate all SIDS deaths.