Aging, Episodic Hypoxia, and Vagal Cardiac Projections.

描述（由申请人提供）：衰老和以慢性间歇性缺氧（CIH）为特征的阻塞性睡眠呼吸暂停综合征通常与高血压、直立性不耐受和心血管疾病的发病率和严重程度增加有关。然而，由于缺乏自主神经末梢和心脏组织内电路的结构信息，我们对这些功能障碍背后的神经机制的理解受到阻碍。到心脏的迷走神经投射来自感觉神经节，即结节神经节，以及脑干中的运动神经元池，即歧义核（NA）和迷走神经背运动核（DmnX）。目前应用的总体目标是确定由衰老，CIH或两者引起的心脏迷走神经控制的功能缺陷，并确定对心脏神经回路的损伤，特别是对心脏的迷走神经轴突的损伤。将测量青年（3个月）、中年（12个月）和老年（24个月）Fischer 344大鼠迷走神经对特定心功能的控制。迷走神经心脏轴突和末端以及NA和DmnX内的谷氨酸能传递将使用一系列技术进行定性和定量检查，这些技术包括顺行神经示踪、体视计数、共聚焦显微镜、神经细胞数字化和双重免疫组织化学。这些解剖结果将与生理反应一起评估，以增强我们对结构-功能关系的理解。目的1将评估与年龄相关的心脏压力反射和迷走神经控制的衰减，以及与心脏和主动脉弓的迷走神经投射相关的结构变化。目的2将评估cih诱导的压力反射敏感性和迷走神经控制的降低以及平行迷走神经心脏轴突变性。目的2还将确定衰老和CIH是否相互作用，诱导迷走神经心脏轴突更严重的功能和解剖损伤。目的3将研究衰老期间和CIH后尾侧脑干复合体（NTS， NA, DmnX）内谷氨酸能传递的变化。总的来说，所提出的实验将推进我们对脑-心相互作用的认识，并为衰老和CIH后迷走神经向心脏组织流出的重塑提供独特的见解。

DESCRIPTION (provided by applicant): Aging and the syndrome of obstructive sleep apnea, which is characterized by chronic intermittent hypoxia (CIH), are commonly associated with increased incidence and severity of hypertension, orthostatic intolerance, and cardiovascular diseases. However, our understanding of the neural mechanisms underlying these dysfunctions is impeded by a lack of structural information on autonomic nerve terminals and the circuitry within the cardiac tissues. Vagal projections to the heart originate from a sensory ganglion, i.e., the nodose ganglion, and the motor neuron pools in the brainstem, i.e., the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). The overall goal of the present application is to determine the functional deficits of the vagal control of the heart induced by aging, CIH, or both, and to identify the damage to the cardiac neural circuitry, specifically to the vagal axonal projections to the heart. Vagal control of particular cardiac functions will be measured in young (3months), middle age (12months) and aged (24 months) Fischer 344 rats. The vagal cardiac axons and terminals, and glutamatergic transmission within the NA and DmnX will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing, stereological counting, confocal microscopy, Neurolucida digitization, and dual immunohistochemistry. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships. Aim 1 will assess aging-associated attenuation of baroreflex and vagal control of the heart, and the associated structural changes of vagal projections to the heart and aortic arch. Aim 2 will evaluate CIH-induced reduction of baroreflex sensitivity and vagal controls and the parallel vagal cardiac axon degeneration. Aim2 will also determine whether aging and CIH interact to induce more severe functional and anatomical damage to the vagal cardiac axons. Aim 3 will study changes in glutamatergic transmission within the caudal brainstem complex (NTS, NA, DmnX) during aging and following CIH. Collectively, the proposed experiments will advance our knowledge of brain-heart interactions and provide unique insights into the remodeling of vagal outflow to cardiac tissues during aging and following CIH.