Sympathetic Neural Regulation and Aging: Medullary Mechanisms and Strategies

描述(申请人提供)：伴随着世界人口的持续增长，老年人的数量也急剧增加。生理功能随着年龄的增长而改变，包括交感神经系统(SNS)调节的深刻变化，支持正常衰老改变交感神经流出调节的概念。然而，增龄对中枢机制调节交感神经放电(SND)的影响仍不清楚。这是一个重大的遗漏，因为在了解正常和病理条件之间的关系之前，了解中枢交感神经回路在正常衰老过程中的变化是必不可少的。本研究计划的目的是确定增龄和从健康衰老状态到衰老的转变如何改变基础条件下和对急性身体应激反应的SND调节的中枢神经机制。我们的基本方法(使用电生理、脑显微注射、分子生物学和蛋白质化学技术)利用中枢神经交感神经调节原理和策略的知识来探索衰老和SND调节之间的基本机制相互作用。拟议的研究将检验这一新的、全面的假设，即：延髓交感神经回路(尾侧加压区、尾侧延髓腹外侧区和延髓头端腹侧外侧区)调节的年龄相关性变化为 调节Fischer 344(F344)大鼠SND调节的年龄相关改变。我们提出了三个工作假设。假设1：增龄使基础SND的髓质调节转变为以增强激活和减少抑制为特征的功能状态。假设2：衰老降低了延髓交感神经回路调节基础SND的反应性和能力。假设3：延髓交感神经回路对急性应激的反应性随着年龄的增长而改变，这表明延髓应对急性应激的策略与年龄有关。这些研究将建立在三个方面的衰老下调节延髓交感神经回路功能的与年龄相关的变化：(1)渐进的健康衰老，(2)衰老，(3)老年(健康/衰老)SNS对急性应激的反应能力。这些发现将对这一领域产生持续而强大的影响，建立新的前沿，将年龄增长对SNS调节机制的影响联系起来，并为确定慢性病发展与SNS功能随年龄相关的变化之间的关系提供洞察力和方向。

DESCRIPTION (provided by applicant): Accompanying the persistent growth in the world's population is a dramatic increase in the number of aged persons. Physiological function is altered with advancing age, including profound changes in the regulation of the sympathetic nervous system (SNS), supporting the concept that normal aging alters the regulation of sympathetic nerve outflow. However, the effects of advancing age on central mechanisms regulating sympathetic nerve discharge (SND) remain unknown. This is a significant omission because understanding how central sympathetic circuits change during normal aging is essential before relationships between normal and pathological conditions can be understood. The objective of the present research plan is to determine how advancing age, and the transition from a healthy aged state to senescence, alters central neural mechanisms regulating SND under basal conditions and in response to acute physical stress. Our basic approach (using electrophysiological, brain microinjection, molecular biological, and protein chemistry techniques) capitalizes on knowledge of central neural sympathetic regulatory principles and strategies to probe the fundamental mechanistic interactions between aging and SND regulation. The proposed studies will test the novel, overall HYPOTHESIS that: Age-dependent changes in the regulation of medullary sympathetic neural circuits (caudal pressor area, caudal ventral lateral medulla, and the rostral ventral lateral medulla) provide the mechanistic basis for mediating age-associated alterations in SND regulation in Fischer 344 (F344) rats. We propose three working hypotheses. Hypothesis 1: Advancing age transforms the medullary regulation of basal SND to a functional state characterized by enhanced activation and reduced inhibition. Hypothesis 2: Senescence reduces the responsivity and capability of medullary sympathetic neural circuits to regulate basal SND. Hypothesis 3: The responsiveness of medullary sympathetic neural circuits to acute stress is altered with advancing age, demonstrating age-related changes in medullary strategies to acute stress. These studies will establish age-related changes in mechanisms regulating the function of medullary sympathetic neural circuits under three aspects of aging: (1) progressive, healthy aging, (2) senescence, and (3) the ability of the aged (healthy/senescent) SNS to respond to acute stress. These findings will exert a sustained and powerful influence on the field by establishing new frontiers relating the effect of advancing age on mechanisms regulating the SNS, and by providing insight and direction for determining relationships between chronic disease development and age-associated changes in SNS function.