Sympathetic activation by intermittent hypoxia

描述(由申请人提供)： 脑桥腹外侧区在短期抑郁(STD)中起关键作用 低氧后的呼吸频率；5-羟色胺和一氧化氮 氧化物，在长期促进(LTF)的发展中发挥作用 在反复缺氧之后。GABAA-细胞内的受体亚单位 控制交感神经激活的桥髓回路(SNA)和 隔神经活动(PNA)表现为以下基因的差异表达 在低氧的条件下。我们的数据表明，呼吸调节 SNA不仅在减少的制剂中发生，而且在数量上 (增加)并在数量上改变其在 在短暂的低氧期间和之后的呼吸周期。因此，我们 假设SNA的上调是由于细胞的可塑性 一项与反复低氧事件相关的呼吸神经系统的研究 设计被称为条件反射。为了检验这一假设，我们提出了一系列 神经生理学和分子生物学实验涉及以下内容 具体目标：1)区分中枢和外周机制 在条件反射后SNA增加的基础上，2)将 短时程增强和抑制(STD)以及长时程易化 (LTF)明显的膈神经活动(PNA)和SNA的变化，以及3)到 GABAA受体亚单位在大鼠脑内的时间表达 本研究设计中控制SNA和PNA的脑干核团，以及4) 两种不同品系啮齿动物CIH条件反射效果的比较 对缺氧和一氧化氮合酶抑制剂的反应。这种方法 提供了一个机会来确定这些动物是否发展成 SNA与低氧反应成正比，以及 交感神经和呼吸控制的可塑性。这些建议的研究 研究与上调相关的神经生理学和分子机制 似乎在临床条件下发生的SNA活动的 与反复缺氧有关；例如，睡眠呼吸暂停和充血性心脏 失败了。

DESCRIPTION (provided by applicant): The ventrolateral pons plays a key role in the short-term depression (STD) in respiratory frequency following hypoxia; and serotonin, as well as nitric oxide, play a part in the development of long-term facilitation (LTF) following repetitive bouts of hypoxia. GABAa-receptor sub-units in the pontomedullary circuits controlling sympathetic nerve activation (SNA) and phrenic nerve activity (PNA) show differential expression of mRNA following conditioning with hypoxia. Our data indicate that respiratory modulation of SNA not only occurs in a reduced preparation but also quantitatively (increases) and quantitatively changes its activation pattern within a breathing cycle during and following brief periods of hypoxia. Thus, we hypothesize that the up-regulation of SNA results from plasticity in the respiratory neural systems associated with repetitive hypoxic events, a study design called conditioning. To test this hypothesis, we propose a series of neurophysiologic and molecular biologic experiments addressing the following specific aims: 1) to differentiate central versus peripheral mechanisms underlying the increases in SNA following conditioning, 2) to correlate the short-term potentiation and depression (STD) as well as long-term facilitation (LTF) evident in phrenic nerve activity (PNA) with changes in SNA, and 3) to characterize the temporal expression of subunits of GABAa receptors in the brainstem nuclei controlling SNA and PNA in this study design, and 4) to compare the effects of CIH conditioning in two rodent strains with different responses to hypoxia and to nitric oxide synthetase inhibitors. This approach provides an opportunity to determine whether these animals develop increased SNA in proportion to the hypoxic response, and the interrelationship of sympathetic and respiratory control plasticity. These proposed studies examine neurophysiologic and molecular mechanisms relevant to the up-regulation of SNA activity which seems to occur in clinical conditions associated with repetitive hypoxia; e.g., sleep apnea and congestive heart failure.