Sympathetic Neural Regulation and Aging: Medullary Mechanisms and Strategies

交感神经调节与衰老：髓质机制和策略

• 批准号: 8439565
• 负责人: Michael J Kenney
• 金额: $ 31.8万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439565
• 关键词: Acute; Age; Aging; Agonist; Area; Binding; Biological; Blood Pressure; Brain; Brain Stem; Chronic Disease; Clinical; Development; Disease; Down-Regulation; Elderly; Equilibrium; Excitatory Amino Acids; Fever; Functional disorder; Growth; Heat Stress Disorders; Kinetics; Knowledge; Lateral; Mediating; Microinjections; Molecular; Molecular Profiling; Nerve; Nervous System Physiology; Neuraxis; Neuromodulator Receptors; Neurons; Neurotransmitter Receptor; Neurotransmitters; Persons; Physiological; Population; Protein Chemistry; Rattus; Real-Time Systems; Regulation; Research; Rest; Series; Stress; Sympathetic Nervous System; System; Techniques; Testing; Up-Regulation; Work; acute stress; age effect; age related; aged; base; body system; experience; frontier; healthy aging; insight; middle age; neural circuit; neuromechanism; neurophysiology; neuroregulation; normal aging; novel; receptor; relating to nervous system; research study; response; senescence; tool

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. PUBLIC HEALTH RELEVANCE: The sympathetic nervous system is critically involved in physiological function and the regulation of this system is markedly changed with advancing age. The proposed studies will determine how aging alters central nervous system mechanisms controlling sympathetic nerve activity. These studies will open new frontiers for understanding age-dependent effects on mechanisms regulating the sympathetic nervous system, and will provide the basis for determining relationships between chronic disease development and age-associated changes in sympathetic function.

描述（由申请人提供）：伴随着世界人口的持续增长，老年人的数量急剧增加。生理功能随着年龄的增长而改变，包括交感神经系统（SNS）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，年龄增长对交感神经放电（SND）中枢机制的影响仍然未知。这是一个重大的遗漏，因为了解中枢交感神经回路在正常衰老过程中如何变化是至关重要的，然后才能理解正常和病理条件之间的关系。 本研究计划的目的是确定年龄的增长，以及从健康的老年状态到衰老的过渡，如何改变基础条件下调节SND的中枢神经机制和对急性身体应激的反应。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。拟议的研究将测试新的总体假设，即：延髓交感神经回路（尾侧加压区，尾侧腹外侧延髓和头侧腹外侧延髓）调节的神经元依赖性变化为以下情况提供了机制基础： 在Fischer 344（F344）大鼠中，介导SND调节的年龄相关改变。我们提出三个工作假设。假设1：随着年龄的增长，髓质对基础SND的调节转变为一种功能状态，其特征是激活增强，抑制减少。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。假设三：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，表明延髓对急性应激的策略与年龄相关。这些研究将在老化的三个方面建立调节延髓交感神经回路功能的机制中的年龄相关变化：（1）进行性健康老化，（2）衰老，和（3）老年（健康/衰老）SNS响应急性应激的能力。这些发现将通过建立与年龄增长对SNS调节机制的影响相关的新前沿，并通过为确定慢性疾病发展与SNS功能中年龄相关变化之间的关系提供见解和方向，对该领域产生持续而强大的影响。 公共卫生相关性：交感神经系统在生理功能中起关键作用，并且该系统的调节随着年龄的增长而显著改变。这项研究将确定衰老如何改变控制交感神经活动的中枢神经系统机制。这些研究将为了解年龄依赖性对交感神经系统调节机制的影响开辟新的前沿，并将为确定慢性疾病发展与交感神经功能年龄相关变化之间的关系提供基础。