THE MEDULLARY SEROTONERGIC SYSTEM: MECHANISMS OF AROUSAL FROM SLEEP

唤醒是婴儿在面临可能危及生命的缺氧时的重要保护机制 在睡眠期间，无论是由于气道阻塞、再呼吸、呼吸暂停还是循环衰竭。我们的重点是 下行或皮层下的唤醒通路，调节呼吸、脊髓运动活动和交感神经活动。 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 婴儿的5-HT 1A受体和5-羟色胺转运体（5-HTT）结合率降低， 神经元，和数量增加的5-HT神经元，在髓质区重要的调节觉醒， 运动活动、体温、心率和呼吸。延髓5-HT神经元也接受兴奋性 食欲素能和抑制性GABA能输入，其本身在唤醒中具有重要作用。我们提出 婴儿猝死综合征婴儿处于危险之中，因为髓质肾上腺素能（5-HT）功能异常， 改变了下行通路的调节，这对协调和有效的唤醒至关重要， 结果从受损的唤醒机制和外在压力的组合，发生在一个 发育的关键阶段，通常在睡眠期间。在分析有缺陷的唤醒机制时， SIDS，重要的是要考虑到许多SIDS婴儿在呼吸道中反复发生呼吸暂停和缺氧。 死亡前几天或几周。我们认为反复暴露于亚临床缺氧会导致觉醒 习惯化习惯化指的是随着时间的推移，对重复刺激的生理反应逐渐减弱， 为了防止对非危险或非重要刺激的不适当反应， 从睡眠中唤醒到危险的刺激，如严重的间歇性缺氧，可能导致灾难性的 后果在这个项目中，我们将定义发育过程中皮层下觉醒的特征， 该大鼠和测试的新的假设，过度习惯化是一个主要的贡献者功能失调 唤醒我们将进一步确定是否有效唤醒睡眠响应缺氧的影响 通过操纵5-HT 1A和GABAA受体以及5-HTT， 缺氧、过热和发烧以及产前暴露于烟草烟雾。我们对穷人的关注 了解皮层下唤醒的功能，病理生理学和神经解剖学，包括其与 温度调节是这个项目的主要优势。这些研究的结果将提供关键信息， 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 缺氧血清素兴奋和婴儿猝死综合症这些信息将是至关重要的，并最终导致 了解SIDS的病理生理机制，并制定治疗干预措施， 消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.