Intertrigeminal region control of apnea

三叉神经区控制呼吸暂停

基本信息

批准号：
7162649
负责人：
MIODRAG G RADULOVACKI
金额：
$ 36.95万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162649
关键词：
Acute Adrenergic Agents Adult Affect Animals Apnea Area Attention Attenuated Automobile Driving Bilateral Biological Neural Networks Brain Stem Breathing Caliber Cell Nucleus Chemosensitization Cholinergic Agents Cholinergic Agonists Classification Conscious Country Data Disease Disease susceptibility Excitatory Amino Acid Antagonists Excitotoxic lesion Glass Glutamate Receptor Glutamates Goals Histologic Ibotenic Acid Injection of therapeutic agent Intravenous Investigation Lateral Lead Lesion Local anesthesia Measurement Measures Mediating Microinjections Monitor Morbidity - disease rate Motor output Neurons Neurotransmitters Numbers Output Pathway interactions Pattern Personal Satisfaction Physiological Pontine structure Population Prosencephalon REM Sleep Rate Rattus Reflex action Reflex control Research Personnel Respiratory System Rodent Model Role Sensory Serotonin Signal Pathway Site Sleep Sleep Apnea Syndromes Sleep Architecture Structure Synapses System Testing Vagus nerve structure Variant Work adrenergic base behavior test cholinergic instrument mammilloinfundibular nucleus structure mortality neurochemistry neuromechanism neurotransmission non rapid eye movement novel pressure programs raphe nuclei rapid eye movement respiratory respiratory reflex response short-term potentiation

项目摘要

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至少影响该国成年人口的3％ - 5％，可用数据表明，这种疾病的显着发病率和死亡率增加。尽管进行了40年的密集调查，但与睡眠有关的呼吸暂停负责或允许的脑干机制仍然未知。我们开发和表征与睡眠相关呼吸障碍的啮齿动物模型的工作使系统地检查呼吸暂停的详细脑干机制是可行的。最近已经证明了一种脑干解剖途径，其中将侧PON的三个侧面区域（ITR）视为呼吸反射的关键调节位点。 ITR受到从第九和第十颅神经接收输入的孤立道的感觉亚核的支配。每种介导气道保护的呼吸暂停反射。此外，ITR将直接的预测发送给延髓产生神经元的呼吸节奏。尽管ITR因此可能代表着重要的气道反射整合位点，但该地区尚未证明生理或病理生理学作用。我们提出了新的初步证据，即ITR会衰减模糊介导的反射呼吸暂停，这种作用似乎是由谷氨酸能神经传递介导的，并且可能是由于短期增强而引起的。此外，我们表明ITR的局灶性病变导致睡眠过程中呼吸暂停的表达急剧增加。该提案的总体目标是1）确定ITR调节呼吸反射的神经机制，2）证明ITR在睡眠呼吸暂停创世纪中的功能作用和3）建立睡眠/尾流状态变化对ITR功能的影响。为了实现这些目标，我们将采用压力显微注射来增强和损害ITR功能活性，并测试ITR功能上单胺能和胆碱能输入的强度。这些操纵对呼吸模式和呼吸反射的急性影响将在麻醉大鼠中进行测试。局灶性病变后的持续作用将通过行为状态和睡眠大鼠的心脏呼吸监测来测试。 ITR提出的神经化学操作提供了一种系统的方法，可以定义该区域在调节反身和自发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传导途径中的初始步骤。