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主要形式，大大增加了发病率和死亡率的风险。许多形式的原发性高血压与交感神经活动（SNA）增强有关，尽管交感神经激活的基础还不清楚。脑中的呼吸调节神经元对SNA具有显著影响，并且在几种高血压模型中存在SNA的与呼吸相关的调制改变。中枢呼吸神经元和那些调节SNA维持动脉压（AP）的神经元之间的联系是完全未知的。该项目将阐明从中枢呼吸神经元到心血管调节神经元的连接，并确定这些与呼吸相关的输入的影响是否在与SNA的呼吸相关调制改变相关的高血压模型中发生变化，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SNA的中枢神经回路，维持AP和精确定位可能导致SNA升高和高血压的改变。这种SNA由头端腹外侧延髓（RVLM）中的神经元驱动，并且RVLM被尾端腹外侧延髓（CVLM）中的GABA能神经元有力地抑制。GABA能CVLM神经元在SNA的压力感受器反射控制中的作用已经很好地建立，但是压力激活的GABA能CVLM神经元也不依赖于压力感受器输入而紧张性地抑制RVLM。在本项目的前一阶段，我们发现麻醉大鼠中单个压力激活的GABA能CVLM神经元显示出不同的神经相关活动模式，尽管这些输入的来源尚不清楚。我们还表明，CVLM是必不可少的，以引起急性缺氧的交感神经相关的反应。这些观察结果表明，CVLM是一个重要的网站，为心脏呼吸的整合和神经系统相关的调节SNA。先前的研究已经确定了2个与脑电相关的区域，它们似乎向CVLM发送神经元能投射，即Kolliker-Nerve核和前Botzinger核。在本更新的目的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-Bronze核和前Botzinger核是否影响压力激活的GABA能CVLM神经元的活性，以及这些输入是否对特定的压力激活的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影响急性缺氧诱导的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的大鼠中CVLM的调节是否改变，慢性间歇性缺氧是人类阻塞性睡眠呼吸暂停的高血压模型。这些研究将产生新的信息，强大的压力感受器独立的影响CVLM神经元，可能会影响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AP调节的影响。 公共卫生相关性：原发性高血压是患者心血管并发症的主要原因。阻塞性睡眠呼吸暂停，导致暴露于慢性间歇性缺氧，存在于30- 50%的原发性高血压患者中，并且大多数睡眠呼吸暂停患者发展为高血压。交感神经活性升高的病因不明是一个贡献者这两种情况。由于睡眠呼吸暂停时观察到的高血压和交感神经活动升高可通过物理改变呼吸而部分缓解，因此更好地了解大脑中呼吸和交感神经活动调节中心之间的耦合对于阐明许多原发性高血压病例的原因和治疗至关重要。

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. PUBLIC HEALTH RELEVANCE: Essential hypertension is a leading cause of cardiovascular complications in patients. Obstructive sleep apnea, which produces exposure to chronic intermittent hypoxia, is present in 30- 50% of patients with essential hypertension, and the majority of patients with sleep apnea develop hypertension. Elevated sympathetic nerve activity of unknown etiology is a contributor to both conditions. Because the hypertension and elevated sympathetic nerve activity observed with sleep apnea are partially alleviated by physically altering breathing, a better understanding of the coupling between regulatory centers in the brain for respiration and sympathetic nerve activity are crucial for elucidating causes and treatment for many cases of essential hypertension.