Blood pressure control by caudal ventrolateral medulla

描述（由申请人提供）：原发性高血压是心血管疾病的一种主要形式，大大增加发病和死亡的风险。许多形式的原发性高血压与交感神经活动增强（SNA）有关，尽管交感神经激活的基础尚不清楚。大脑中的呼吸调节神经元对 SNA 具有显着影响，并且在几种高血压模型中存在与呼吸相关的 SNA 调节的改变。中枢呼吸神经元与调节维持动脉压 (AP) 的 SNA 的神经元之间的联系完全未知。该项目将阐明中枢呼吸神经元与心血管调节神经元的连接，并确定这些呼吸相关输入的影响是否在高血压模型中发生变化，该模型与 SNA 呼吸相关调节的改变有关，即暴露于慢性间歇性缺氧 (CIH)。 这项研究的长期目标是阐明调节维持 AP 的 SNA 的中枢神经回路，并查明可能导致 SNA 升高和高血压的改变。该 SNA 由头侧腹外侧延髓 (RVLM) 中的神经元驱动，而 RVLM 受到尾侧腹外侧延髓 (CVLM) 中的 GABA 能神经元的强烈抑制。 GABA 能 CVLM 神经元在 SNA 压力感受反射控制中的作用已得到充分证实，但压力激活的 GABA 能 CVLM 神经元也会独立于压力感受器输入而强直地抑制 RVLM。在该项目的前一阶段，我们发现麻醉大鼠中单个气压激活的 GABA 能 CVLM 神经元表现出不同的呼吸相关活动模式，尽管这些输入的来源尚不清楚。我们还表明，CVLM 对于激发对急性缺氧的呼吸相关交感神经反应至关重要。这些观察结果表明 CVLM 是心肺整合和 SNA 呼吸相关调节的重要部位。先前的研究已经确定了 2 个与呼吸相关的区域，它们似乎向 CVLM 发送谷氨酸能投射，即 Kolliker-Fuse 核和前 Botzinger 核。在本次更新的目标 1 和 2 中，我们将在麻醉大鼠中进行电生理学实验，以确定 Kolliker-Fuse 和 pre-Botzinger 核是否影响气压激活的 GABA 能 CVLM 神经元的活性，以及​​这些输入是否对特定气压激活的 CVLM 神经元或呼吸周期的阶段具有选择性。我们还将确定这些输入是否会影响急性缺氧引起的 CVLM 神经元活动和 SNA 的变化。在目标 3 和 4 中，我们将确定暴露于慢性间歇性缺氧（人类阻塞性睡眠呼吸暂停的高血压模型）的大鼠中 CVLM 的调节是否发生改变。这些研究将产生关于对 CVLM 神经元的强大的独立于压力感受器的影响的新信息，这些神经元可能影响 RVLM、SNA 和 AP。此外，这些研究将进一步了解心肺整合对健康和高血压中 AP 调节的影响。

DESCRIPTION (provided by applicant): Essential hypertension is a leading form of cardiovascular disease that greatly increases the risks of morbidity and mortality. Many forms of essential hypertension are associated with augmented sympathetic nerve activity (SNA), although the basis of the sympatho-activation is not well understood. Respiratory regulatory neurons in the brain provide a significant influence on SNA, and altered respiratory-related modulation of SNA is present in several models of hypertension. Links between central respiratory neurons and those that regulate the SNA that maintains arterial pressure (AP) are completely unknown. This project will elucidate connections from central respiratory neurons to cardiovascular regulatory neurons and determine whether the influences of these respiratory-related inputs are changed in a hypertensive model associated with altered respiratory-related modulation of SNA, namely exposure to chronic intermittent hypoxia (CIH). The long range goals of this research are to elucidate central neural circuits that regulate the SNA that maintains AP and pinpoint alterations that may lead to elevated SNA and hypertension. This SNA is driven by neurons in the rostral ventrolateral medulla (RVLM), and the RVLM is powerfully restrained by GABAergic neurons in the caudal ventrolateral medulla (CVLM). The role of GABAergic CVLM neurons in the baroreflex control of SNA is well established, but baro-activated GABAergic CVLM neurons also tonically inhibit the RVLM independent of baroreceptor inputs. In the previous period of this project we showed that individual baro-activated GABAergic CVLM neurons in anesthetized rats display distinct patterns of respiratory-related activity, though sources of these inputs are unknown. We also showed the CVLM is essential to evoke respiratory-related sympathetic responses to acute hypoxia. These observations suggest the CVLM is an important site for cardio-respiratory integration and respiratory-related regulation of SNA. Previous studies have identified 2 respiratory-related regions that appear to send glutamatergic projections to the CVLM, namely the Kolliker-Fuse nucleus and the pre-Botzinger nucleus. In Aims 1 and 2 of this renewal we will perform electrophysiological experiments in anesthetized rats to determine whether the Kolliker-Fuse and pre- Botzinger nuclei influence the activity of baro-activated GABAergic CVLM neurons, and whether these inputs are selective for particular baro-activated CVLM neurons or phases of the respiratory cycle. We will also determine whether these inputs impact acute hypoxia-induced changes in CVLM neuronal activity and SNA. In Aims 3 and 4 we will determine whether regulation of the CVLM is altered in rats exposed to chronic intermittent hypoxia, a hypertensive model for obstructive sleep apnea in humans. These studies will produce novel information regarding a powerful baroreceptor-independent influence upon the CVLM neurons that are likely to influence the RVLM, SNA, and AP. In addition, these studies will further our understanding of the impact of cardio-respiratory integration upon the regulation of AP in health and hypertension.