Alterations in chemoafferent integration induced by chronic intermittent hypoxia

描述（由申请人提供）：慢性暴露于间歇性缺氧（CIH）是一种广泛使用的动物模型，用于睡眠呼吸暂停期间发生的动脉低氧血症。动物体内的CIH已被证明会导致血压升高，就像在人类睡眠呼吸暂停患者中看到的那样，这种高血压依赖于交感神经系统（SNS）和血管紧张素（Angll）。目前对cih诱导的高血压的解释包括：动脉化学受体激活为交感神经放电持续增加提供驱动力。孤立束核（NTS）是动脉化学感受器传入纤维的主要中枢神经系统终止部位。该项目的总体假设是，CIH对动脉化学感受器的重复激活增加了NTS中调节交感神经和下丘脑轴功能的神经元的放电和反应性。肾上腺皮质酮（CORT）在急性缺氧暴露后增加。CORT已被证明可以增强中央给药的Angll的加压作用，NTS内的Angll促进突触和化学反射反应。据推测，增强的Angll介导的反应（钙内流增加）导致对兴奋性递质AMPA的反应增强。因此，NTS神经元对动脉化学受体输入的敏感性增强，这有助于在CIH后观察到血压、交感神经放电和交感反应性的升高。据推测，尾部NTS中的儿茶酚胺能（A2）和谷氨酸能神经元是这些改变发生的主要部位。具体目标1：第一个目标是表征NTS神经元在暴露于CIH时如何反应和适应，以及缺氧在介导/调节对化学受体传入输入的反应中的作用。具体目标2：第二个目标是确定糖皮质激素II型受体作为NTS神经元这些适应性变化的介质的作用。具体目标3：第三个目标是确定血管紧张素在CIH诱导的NTS神经元改变中的作用。这些研究结果将为CIH导致血压升高、交感神经放电和交感神经反应性的机制提供新的见解。这些因素介导了许多与睡眠呼吸暂停相关的病理，包括高血压、不良心血管事件风险增加和胰岛素抵抗。

DESCRIPTION (provided by applicant): Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during sleep apnea. CIH in animals has been shown to result in an increased blood pressure as seen in human sleep apnea patients and this hypertension is dependent upon the sympathetic nervous system (SNS) and angiotensin (Angll). Current explanations for CIH-induced hypertension include arterial chemoreceptor activation providing a driving force for a persistent increase in sympathetic nerve discharge. The nucleus of the solitary tract (NTS) is the primary CNS site of termination of arterial chemoreceptor afferent fibers. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors by CIH increases the discharge of and the responsiveness of neurons in the NTS that regulate sympathetic and HPA axis function. The adrenal steroid corticosterone (CORT) has been shown to be increased following acute exposures to hypoxia. CORT has been shown to enhance the pressor effect of centrally administered Angll and Angll within the NTS facilitates synaptic and chemoreflex responses. It is hypothesized that enhanced Angll mediated responses (increased calcium influx) result in enhanced responses to the excitatory transmitter AMPA. As a result, the sensitivity of NTS neurons to arterial chemoreceptor inputs is enhanced which contributes to the elevations in blood pressure, sympathetic nerve discharge and sympathetic reactivity observed after CIH. It is hypothesized that catecholaminergic (A2) and glutamatergic neurons in the caudal NTS are the primary sites where these alterations occur. Specific Aim 1: The first goal is to characterize how NTS neurons respond and adapt during exposure to CIH and the role of hypoxia in mediating/modulating responses to chemoreceptor afferent inputs. Specific Aim 2: The second goal is to determine the role of the glucocorticoid Type II receptor as a mediator of these adaptive changes in NTS neurons. Specific Aim 3: The third goal is to determine the role of angiotensin in the alterations in NTS neurons induced by CIH. The results of these studies will provide new insights into the mechanisms whereby CIH leads to elevated blood pressure, sympathetic nerve discharge and sympathetic reactivity. These factors mediate much of the pathology associated with sleep apnea including hypertension, increased risk of adverse cardiovascular events and insulin resistance.