Aging, Episodic Hypoxia, and Vagal Cardiac Projections.

描述（由申请人提供）：衰老和阻塞性睡眠呼吸暂停综合征（以慢性间歇性缺氧（CIH）为特征）通常与高血压、立位不耐受和心血管疾病的发病率和严重程度增加相关。 然而，我们对这些功能障碍背后的神经机制的理解受到缺乏心脏组织内自主神经末梢和电路的结构信息的阻碍。到心脏的迷走神经投射源自感觉神经节，即，结状神经节和脑干中的运动神经元池，即，疑核（NA）和迷走神经背侧运动核（DmnX）。 本申请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，并鉴定对心脏神经回路的损伤，特别是对心脏的迷走神经轴突投射的损伤。 将在年轻（3个月）、中年（12个月）和老年（24个月）Fischer 344大鼠中测量特定心脏功能的迷走神经控制。 迷走神经的心脏轴突和终端，并在NA和DMnX内的mamatergic传输将进行定性和定量检查使用的技术，将包括顺行神经示踪，体视学计数，共聚焦显微镜，Neurolucida数字化，和双重免疫组化电池。 这些解剖学发现将结合生理反应进行评估，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压力反射衰减和迷走神经控制的心脏，以及相关的结构变化的迷走神经投射到心脏和主动脉弓。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减少和平行的迷走神经心脏轴突变性。 Aim 2还将确定衰老和CIH是否相互作用以诱导对迷走神经心脏轴突的更严重的功能和解剖损伤。 目的3研究衰老过程中和CIH后尾侧脑干复合体（NTS，NA，DmnX）内神经递质传递的变化。 总的来说，拟议的实验将推进我们的知识，脑心相互作用，并提供独特的见解迷走神经流出到心脏组织在老化和CIH后的重塑。

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.