Aging, Episodic Hypoxia, and Vagal Cardiac Projections.

描述(申请人提供)：衰老和以慢性间歇性低氧(CIH)为特征的阻塞性睡眠呼吸暂停综合征通常与高血压、立位不耐受和心血管疾病的发病率和严重性增加有关。然而，由于缺乏关于自主神经末梢和心脏组织内回路的结构信息，我们对这些功能障碍的神经机制的理解受到阻碍。迷走神经向心脏的投射来自感觉神经节(即结状神经节)和脑干的运动神经元池，即疑核(NA)和迷走神经背核(DmnX)。本申请的总体目标是确定衰老、脑出血或两者同时引起的心脏迷走神经控制的功能缺陷，并确定心脏神经回路的损害，特别是迷走神经轴突向心脏的投射。将在年轻(3个月)、中年(12个月)和老年(24个月)Fischer 344大鼠身上测量特定心脏功能的迷走神经控制。将使用一系列技术对迷走神经轴突和终末以及NA和DmnX内的谷氨酸能传递进行定性和定量检测，这些技术将包括顺行神经追踪、体视学计数、共聚焦显微镜、神经荧光素数字化和双重免疫组织化学。这些解剖学发现将结合生理反应进行评估，以加强我们对结构-功能关系的理解。目的1将评估与年龄相关的压力感受性反射减弱和心脏迷走神经控制，以及迷走神经投射到心脏和主动脉弓的相关结构变化。目的2将评价CIH引起的压力感受性反射敏感性和迷走神经控制的降低以及平行迷走神经的心脏轴突变性。AIM2还将确定衰老和脑出血是否相互作用，导致迷走神经心脏轴突受到更严重的功能和解剖损伤。目的3将研究衰老和脑出血后尾侧脑干复合体(NTS，NA，DmnX)内谷氨酸能传递的变化。总之，拟议的实验将促进我们对脑心相互作用的了解，并为在衰老和脑出血后迷走神经流出到心脏组织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.