Chemoanatomic changes associated with aging in vestibulo-sympathetic pathways

与前庭交感神经通路衰老相关的化学解剖学变化

• 批准号: 8107476
• 负责人: Gay R Holstein
• 金额: $ 17.31万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107476
• 关键词: Adverse effects; Age; Aging; Anatomy; Animals; Antihypertensive Agents; Area; Baroreflex; Blood Pressure; Brain Stem; Cell Nucleus; Chemicals; Clinical; Complex; Data; Depressed mood; Disinhibition; Dizziness; Elderly; Epinephrine; Future; Glutamates; Goals; Heart Rate; High Prevalence; Human; Image; Immunofluorescence Immunologic; Label; Literature; Measures; Mediating; Modification; Movement; Mus; Neurons; Neurotransmitters; Nitric Oxide; Norepinephrine; Nuclear; Nucleus solitarius; Organ; Orthostatic Hypotension; Outcome; Pathway interactions; Pattern; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Population; Posture; Pressoreceptors; Process; Production; Proteins; Publishing; Rattus; Reflex action; Reporting; Research; Reticular Formation; Rodent; Rodent Model; Signal Transduction; Site; Source; Stress; Structure; Syncope; Syndrome; System; Tachycardia; Testing; Vertigo; Work; age effect; age group; age related; aged; base; blood pressure regulation; body position; fall risk; falls; flexibility; gamma-Aminobutyric Acid; imidazoleacetic acid ribotide; interest; loss of function; medial vestibular nucleus; mortality; nerve supply; otoconia; protein expression; public health relevance; response; young adult

DESCRIPTION (provided by applicant): Changes in body position and posture are detected by the vestibular system and are normally accompanied by rapid modifications in blood pressure. These compensatory adjustments, which allow humans to stand up without fainting, are mediated by functional integration of the vestibular system and blood pressure control mechanisms in the caudal medullary reticular formation: signals from the vestibular otolith organs provide the primary source of input to the shorter latency vestibulo-sympathetic reflex (VSR), while arterial baroreceptors regulate sympathetic tone via the relatively long- latency baroreflex. Although the clinical literature has consistently reported a decline in vestibulo-autonomic function with age, and this decline is associated with increased risk of falling and increased mortality in older people, the cellular mechanisms underlying this loss of function are not known. The overall goal of this two-year exploratory project is to identify chemoanatomic alterations in key caudal brainstem sites of aged rodents, correlated with assessment of VSR and baroreflex function. The two specific aims are (1) to obtain physiological measures of autonomic activity, particularly heart rate and blood pressure (a) under baseline conditions, (b) in response to baroreflex activation and (c) in response to vestibular stimulation in young-adult and aged rats and mice; and (2) to visualize Fos protein, and transmitter and modulator expression in medullary regions activated by the three conditions of Aim 1, in young adult and aged rats and mice. This research will evaluate the overall hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in VSR and baroreflex control of blood pressure. The project will also assess the utility of two common rodent models of aging for studies of vestibulo-autonomic structure and function. PUBLIC HEALTH RELEVANCE: Rapid adjustments in blood pressure normally accompany movements and changes in body position and posture; these compensatory adjustments allow humans to stand up without fainting. Orthostatic hypotension, which is highly prevalent in the elderly, occurs when the vestibulo-sympathetic reflex fails to mediate such compensatory adjustments. This project will evaluate the hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in vestibulo-sympathetic- and baroreflex control of blood pressure, thereby suggesting new pharmacotherapies to ameliorate orthostatic hypotension and more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.

描述（由申请人提供）：前庭系统检测到身体位置和姿势的变化，并且通常伴随着血压的快速变化。这些补偿性调整使人类能够站起来而不晕倒，是由前庭系统的功能整合和尾髓网状结构中的血压控制机制介导的：来自前庭耳石器官的信号提供了较短潜伏期的主要输入源前庭交感反射（VSR），而动脉压力感受器通过相对较长潜伏期的压力反射调节交感神经张力。尽管临床文献一致报道前庭自主功能随着年龄的增长而下降，并且这种下降与老年人跌倒风险增加和死亡率增加有关，但这种功能丧失背后的细胞机制尚不清楚。这个为期两年的探索性项目的总体目标是确定老年啮齿动物尾部脑干关键部位的化学解剖学改变，并与 VSR 和压力感受反射功能的评估相关。两个具体目标是（1）获得自主活动的生理测量，特别是心率和血压（a）在基线条件下，（b）对压力反射激活的反应和（c）对年轻成人前庭刺激的反应以及老年大鼠和小鼠； (2) 观察年轻成年和老年大鼠和小鼠中由目标 1 的三种条件激活的髓质区域中 Fos 蛋白、递质和调节剂的表达。这项研究将评估总体假设，即尾髓质化学解剖学的特定改变与年龄依赖性 VSR 和血压压力反射控制的下降平行。该项目还将评估两种常见的啮齿动物衰老模型在前庭自主结构和功能研究中的效用。 公共卫生相关性：血压的快速调整通常伴随着身体位置和姿势的运动和变化；这些补偿性调整使人类能够站起来而不会晕倒。当前庭交感神经反射不能介导这种代偿性调节时，就会发生直立性低血压，这种情况在老年人中非常普遍。该项目将评估以下假设：尾髓质化学解剖学的特定改变与年龄依赖性的前庭交感神经和压力反射控制血压的下降平行，从而提出改善直立性低血压的新药物疗法和更具体的抗高血压药物不会引起头晕和眩晕等前庭功能障碍的副作用。