Chemoanatomic changes associated with aging in vestibulo-sympathetic pathways

描述（由申请人提供）：体位和姿势的变化由前庭系统检测，通常伴随着血压的快速变化。这些补偿性调节使人类能够站立而不昏厥，通过前庭系统和尾侧延髓网状结构中的血压控制机制的功能整合来介导：来自前庭耳石器官的信号提供了较短潜伏期前庭交感神经反射（VSR）的主要输入源，而动脉压力感受器通过相对长潜伏期的压力感受器反射调节交感神经紧张。尽管临床文献一直报道前庭自主神经功能随年龄增长而下降，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侧脑干关键部位的化学解剖学改变，与VSR和压力反射功能的评估相关。两个具体目的是（1）获得自主活动的生理测量，特别是在成年和老年大鼠和小鼠中（a）在基线条件下，（B）响应压力反射激活和（c）响应前庭刺激的心率和血压;和（2）观察由Aim 1，在年轻成年和老年大鼠和小鼠中。这项研究将评估的总体假设，具体的变化，在化学解剖的尾部延髓平行的年龄依赖性下降VSR和压力反射控制血压。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神经结构和功能研究中的实用性。 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。直立性低血压在老年人中非常普遍，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。本项目将评估以下假设：延髓尾侧化学解剖的特定改变与前庭交感神经和压力反射控制血压的年龄依赖性下降平行，从而提出新的药物疗法来改善直立性低血压和更具体的抗高血压药物，这些药物不会引起前庭副作用，如头晕和眩晕。

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.