Blood pressure control by caudal ventrolateral medulla

描述（申请人提供）：大脑通过自主神经系统在动脉压（AP）的调节中起重要作用。申请人的长期目标是了解中枢神经系统（CNS）在正常AP条件下如何控制交感血管舒缩张力，以及高血压如何改变其功能。许多形式的高血压与交感神经活动（SNA）升高有关，尽管这种交感神经激活的基础尚不清楚。正常情况下，SNA受到尾侧腹外侧髓质（CVLM） GABAergic神经元的抑制，以维持一致的AP。对于SNA和AP的短期控制，这些GABAergic CVLM神经元是压力感受器反射中枢通路中的重要环节。然而，gaba能的CVLM神经元对于设定独立于气压反射的SNA的长期水平显然也很重要。我们观察到，在长期缺乏压力感受器输入或其在孤束核（NTS）的终止位点的情况下，恢复正常的平均AP与正常的cvlm介导的SNA和AP抑制有关。相反，自发性高血压大鼠的SNA升高可能与cvlm介导的SNA和AP抑制受损有关。对于调节这些强大的gaba能CVLM神经元活动的中枢机制知之甚少。该项目将在大鼠身上使用最先进的方法（即电生理学，神经解剖学和分子方法）来确定大脑的其他区域如何在正常和高血压条件下调节gaba能CVLM神经元的活动。具体来说，我们将确定下丘脑室旁核和腹外侧导水管周围灰质是否激活投射到腹外侧髓质吻侧（RVLM）的gaba能CVLM神经元。我们将使用慢性动脉压力感受器失神经大鼠作为血压正常的模型来检查gaba能CVLM神经元的输入，这些神经元可能被强大的压力感受器输入所掩盖。此外，我们将确定cvlm介导的SNA抑制是否在自发性高血压大鼠中受损。总的来说，这些研究将为脑干在交感血管舒缩张力和AP的长期调节中的作用提供复杂的机制分析，并将确定慢性压力感受器去神经支配和自发性高血压发生的功能变化。

DESCRIPTION (provided by applicant): The brain plays an important role in the regulation of arterial pressure (AP) via the autonomic nervous system. The long range goal of the applicant is to understand how the central nervous system (CNS) controls sympathetic vasomotor tone under conditions of normal AP and how the function is altered with hypertension. Many forms of hypertension are linked with elevated sympathetic nerve activity (SNA), although the basis of this sympatho-activation is not well understood. Normally, SNA is restrained by GABAergic neurons in the caudal ventrolateral medulla (CVLM) to maintain a consistent AP. For the short-term control of SNA and AP, these GABAergic CVLM neurons are an essential link in the central pathway for the baroreceptor reflex. However, GABAergic CVLM neurons also are clearly important for setting the long-term level of SNA independent of the baroreflex. We have observed that in the chronic absence of baroreceptor inputs or their site of termination in the nucleus tractus solitarius (NTS), the restoration of a normal mean AP is associated with a normal CVLM-mediated inhibition of SNA and AP. In contrast, spontaneously hypertensive rats have elevated SNA which may be linked with impaired CVLM-mediated inhibition of SNA and AP. Apart from baroreceptor inputs and the NTS, little is known about the central mechanisms regulating the activity of these powerful GABAergic CVLM neurons. This project will use a combination of state-of-the-art methods in rats (i.e. electrophysiological, neuroanatomical, and molecular approaches) to determine how other areas of the brain regulate the activity of GABAergic CVLM neurons under normotensive and hypertensive conditions. Specifically, we will determine whether identified glutamatergic inputs to the CVLM from the paraventricular nucleus of the hypothalamus and ventrolateral periaqueductal gray activate GABAergic CVLM neurons that project to the rostral ventrolateral medulla (RVLM). We will use chronic arterial baroreceptor denervated rats as a normotensive model to examine inputs to GABAergic CVLM neurons that may be masked by powerful baroreceptor inputs. In addition, we will determine whether the CVLM-mediated inhibition of SNA is impaired in spontaneously hypertensive rats. Collectively, these studies will provide a sophisticated analysis of the mechanisms underlying the brainstem's role in the long-term regulation of sympathetic vasomotor tone and AP and will determine functional changes that occur with chronic baroreceptor denervation and spontaneous hypertension.