Sympathetic Neural Regulation and Aging: Medullary Mechanisms and Strategies

描述（由申请人提供）：随着世界人口的持续增长，老龄人口数量急剧增加。生理功能随着年龄的增长而改变，包括交感神经系统（SNS）的调节发生了深刻的变化，这支持了正常衰老改变交感神经流出调节的概念。然而，年龄增长对调节交感神经放电（SND）的中枢机制的影响尚不清楚。这是一个重要的遗漏，因为在理解正常和病理条件之间的关系之前，理解正常衰老过程中中枢交感神经回路的变化是必不可少的。本研究计划的目的是确定年龄的增长，以及从健康老年状态到衰老的转变，如何改变基础条件下调节SND的中枢神经机制，以应对急性身体应激。我们的基本方法（使用电生理学，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。提出的研究将检验一个新颖的、全面的假设：年龄依赖性的髓质交感神经回路（尾侧压迫区、尾侧侧侧延髓和吻侧侧侧侧侧侧延髓）的调节变化提供了机制基础

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.