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: 8718970
• 负责人: Michael J Kenney
• 金额: $ 30.75万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718970
• 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; Functional disorder; Growth; Heat Stress Disorders; Hyperthermia; 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.

描述（由申请人提供）：伴随着世界人口的持续增长是老年人人数的急剧增加。随着年龄的增长，生理功能会改变，包括对交感神经系统（SNS）调节的深刻变化，支持正常衰老会改变交感神经流出调节的概念。但是，促进年龄对调节交感神经排出（SND）的中心机制的影响仍然未知。这是一个重大的遗漏，因为在正常衰老和病理状况之间的关系之前，了解正常衰老期间中心交感神经的变化是必不可少的。 本研究计划的目的是确定年龄的进步以及从健康的老年状态到衰老的过渡，从而改变了基础条件下调节SND的中心神经机制，并响应急性身体压力。我们的基本方法（使用电生理学，大脑显微注射，分子生物学和蛋白质化学技术）利用了中心神经交感神经调节原理和策略，以探测衰老与SND调节之间的基本机械相互作用。拟议的研究将检验新的总体假设：髓质交感神经回路调节的年龄依赖性变化（尾部压力区域，尾骨腹侧髓质和the Rostral腹侧髓质）为机械基础提供了机械基础。 Fischer 344（F344）大鼠中介导与年龄相关的变化。我们提出了三个工作假设。假设1：促进年龄将基础SND的髓质调节转化为功能状态，其特征是激活和抑制减少。假设2：衰老降低了髓质交感神经回路调节基础SND的反应性和能力。假设3：随着年龄的增长，髓质交感神经回路对急性压力的反应性发生了变化，证明了与年龄相关的髓质策略变化到急性压力。这些研究将建立与年龄相关的机制变化，从而在衰老的三个方面下调节髓质交感神经回路的功能：（1）逐步，健康的衰老，（2）衰老，以及（3）衰老（健康/衰老）SNS对急性应激的反应的能力。这些发现将通过建立新的边界来对该领域产生持续和强大的影响，从而将年龄对调节SNS的机制的影响，并为确定慢性疾病发展与SNS功能的年龄相关变化之间的关系提供洞察力和方向。