SENESCENCE ALTERS SYMPATHETIC REGULATION TO HEAT STRESS

在热浪期间，老年人会因体温过高和心血管疾病而过度死亡，然而，其相关机制尚不清楚。由于交感神经系统在心血管对热应激的调节中起着关键作用，我们假设衰老大鼠的心血管对热的改变可能是交感神经调节的年龄相关变化所致。与这一假设一致，我们的初步数据显示，在衰老过程中，肾脏交感神经放电(SND)对急性热应激的反应减弱。(24个月大)与成熟(10个月大)F344大鼠相比；然而，其相关机制尚不清楚。拟议中的研究将确定老年大鼠SND对热应激反应减弱的机制。具体目标1：检验老年大鼠静息状态下传出SND水平不代表生理最大值或最小值的假设。具体目标2：确定衰老是否会改变SND调节机制，从而在衰老的F344大鼠与成熟的F344大鼠相比，在热应激期间使用不同的神经策略。我们将检验假设：a)与成熟大鼠相比，高温诱导的交感兴奋和交感抑制反应减弱；b)衰老与交感神经回路的反应特征在TC升高期间发生变化有关，这体现在SND爆发模式没有改变；以及c)在衰老但未成熟的F344大鼠的急性加热过程中，内脏器官和尾部血流保持不变。具体目标3：测试衰老大鼠的急性加热激活选定的体温调节效应器的假设。具体目标4：确定前脑神经回路，特别是下丘脑室旁核，是否在抑制衰老大鼠对热应激的SND反应中起关键作用。将使用电生理学、中枢神经系统损伤和灌注以及频域分析技术来完成这些研究。这项拟议的研究将首次提出一种假设，即交感神经回路对热应激做出反应的工作策略会随着年龄的增长而改变。

Excess mortality from hyperthermia and cardiovascular disease occurs in aged humans during heat waves, however, responsible mechanisms are poorly understood. Because the sympathetic nervous system plays a critical role in cardiovascular regulation to heat stress, we hypothesize that cardiovascular alterations to heating in senescent rats may result from age-related changes in sympathetic nerve regulation. Consistent with this hypothesis, our preliminary data demonstrate that renal sympathetic nerve discharge (SND) responses to acute heat stress are attenuated in senescent. (24-month-old) compared with mature (10-month-old) F344 rats; however the responsible mechanisms are not well understood. The proposed studies will determine mechanisms responsible for the diminished SND responses to heat stress in aged rats. Specific Aim 1: Test the hypothesis that levels of efferent SND at rest in senesent rats do not represent the physiological maximum or minimum. Specific Aim 2: To determine if aging alters SND regulatory mechanisms such that different neural strategies are used during heat stress in senescent compared to mature F344 rats. We will test the hypotheses that: a) hyperthermia-induced sympathoexcitatory and sympathoinhibitory responses are attenuated in senescent compared to mature rats, b) aging is associated with changes in the response characteristics of sympathetic neural circuits during increased Tc as demonstrated by the lack of alterations in the SND bursting pattern, and c) visceral organ and tail blood flows remain unchanged during acute heating in senescent but not mature F344 rats. Specific Aim 3: Test the hypothesis that acute heating in senescent rats activates selected thermoregulatory effectors. Specific Aim 4: To determine if forebrain neural circuits, specifically the paraventricular nucleus of the hypothalamus, are critically involved in suppressing SND responses to heat stress in senescent rats. Electrophysiological, CNS lesioning and perfusion, and frequency-domain analytical techniques will be used to complete these studies. The proposed studies will, for the first time, advance the hypothesis that the working strategies employed by sympathetic neural circuits to respond to heat stress are modified by aging.