Intertrigeminal region control of apnea

三叉神经区控制呼吸暂停

• 批准号: 6838243
• 负责人: MIODRAG G RADULOVACKI
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838243
• 关键词: REM sleep; acetylcholine; biological signal transduction; brain electrical activity; brain mapping; electroencephalography; electromyography; experimental brain lesion; glutamate receptor; laboratory rat; microinjections; neural plasticity; neural transmission; neuroregulation; neurotransmitter antagonist; plethysmography; pons; receptor expression; respiration regulatory center; respiratory reflex; serotonin; sleep apnea; solitary tract nucleus

DESCRIPTION (provided by applicant): Sleep apnea syndrome affects at least 3% - 5% of the adult population in this country and available data suggest that significant morbidity and increased mortality result from this disorder. Despite 40 years of intensive investigation, the brainstem mechanisms responsible for, or permissive of, sleep-related apnea remain unknown. Our work to develop and characterize a rodent model of sleep-related breathing disorder makes it feasible to systematically examine the detailed brainstem mechanisms of apnea. A brainstem anatomical pathway recently has been demonstrated in which the intertrigeminal region (ITR) of the lateral pons is posited as a key regulatory site for apneic reflexes. The ITR is innervated by sensory subnuclei of the solitary tract that receive inputs from the ninth and tenth cranial nerves; each of which mediate airway-protective apneic reflexes. Moreover, the ITR sends direct projections to respiratory rhythm generating neurons in the medulla. Although the ITR thus may represent an important airway reflex integrating site, no physiological or pathophysiological role has yet been demonstrated for this region. We present novel preliminary evidence that the ITR dampens vagally-mediated reflex apnea, an effect that appears to be mediated by glutamatergic neurotransmission and may result from short term potentiation. Further, we show that focal lesions of the ITR lead to dramatically increased apnea expression during sleep. The overall goals of this proposal are 1) to identify the neural mechanisms by which the ITR modulates apneic reflexes, 2) to demonstrate the functional role of the ITR in sleep apnea genesis and 3) to establish the impact of sleep/wake state changes on ITR function. To achieve these goals, we will employ pressure microinjections to enhance and impair ITR functional activity and to test the strength of monoaminergic and cholinergic inputs on ITR function. The acute impact of these manipulations on respiratory pattern and apneic reflexes will be tested in anesthetized rats. Sustained effects following focal lesions will be tested by behavioral state and cardiorespiratory monitoring in sleeping rats. The proposed neurochemical manipulations of the ITR provide a systematic approach to define the importance of this region in modulating both reflexive and spontaneous sleep-related apnea and to identify the initial steps in the signaling pathway by which this region modulates apnea expression.

描述（由申请人提供）：睡眠呼吸暂停综合征影响该国至少 3% - 5% 的成年人口，现有数据表明，这种疾病会导致显着的发病率和死亡率的增加。尽管经过 40 年的深入研究，导致或允许睡眠相关呼吸暂停的脑干机制仍然未知。我们开发和表征睡眠相关呼吸障碍的啮齿动物模型的工作使得系统地检查呼吸暂停的详细脑干机制成为可能。最近已经证明了脑干解剖通路，其中脑桥外侧的三叉神经区（ITR）被认为是呼吸暂停反射的关键调节部位。 ITR 受孤束感觉亚核支配，接收来自第九和第十脑神经的输入；其中每一个都介导气道保护性呼吸暂停反射。此外，ITR 向髓质中产生呼吸节律的神经元发送直接投射。因此，尽管 ITR 可能代表重要的气道反射整合位点，但尚未证明该区域的生理或病理生理作用。我们提出了新的初步证据，表明 ITR 抑制迷走神经介导的反射性呼吸暂停，这种效应似乎是由谷氨酸能神经传递介导的，可能是短期增强的结果。此外，我们发现 ITR 的局灶性病变会导致睡眠期间呼吸暂停表达显着增加。该提案的总体目标是 1) 确定 ITR 调节呼吸暂停反射的神经机制，2) 证明 ITR 在睡眠呼吸暂停发生中的功能作用，3) 确定睡眠/觉醒状态变化对呼吸暂停反射的影响。 ITR功能。为了实现这些目标，我们将采用压力显微注射来增强和削弱 ITR 功能活性，并测试单胺能和胆碱能输入对 ITR 功能的强度。这些操作对呼吸模式和呼吸暂停反射的急性影响将在麻醉大鼠中进行测试。将通过睡眠大鼠的行为状态和心肺监测来测试局灶性损伤后的持续效果。所提出的 ITR 神经化学操作提供了一种系统方法来定义该区域在调节反射性和自发性睡眠相关呼吸暂停中的重要性，并确定该区域调节呼吸暂停表达的信号通路中的初始步骤。