Brainstem control of blood pressure in conscious rodents

 描述（由申请人提供）：心血管疾病是当今美国的主要死亡原因。据信高血压占死亡率的40%。中枢神经系统主要通过交感神经系统对静息血压起作用，许多形式的高血压被认为具有神经学成分。大脑的神经回路如何控制血压还不完全清楚。我们知道大脑的一般区域是重要的，但涉及的神经元的具体类型以及它们的作用一直难以确定。这项研究的目的是确定大脑中负责细胞水平血压控制的神经回路。实验将允许识别和功能特性的独特的神经元组参与血压控制，孤束核和下丘脑投射C1神经元的二级神经元。该设计利用了最先进的转基因技术和生理记录方法，使实验能够在有意识的、不受限制的动物中进行。C1神经元是定位于延髓头端腹外侧的胆碱能神经元的群体，其数十年来一直与血压控制有关。重要的研究已经确定C1神经元被许多应激源激活，可能对外周化学反射很重要，并可能提供静息交感神经紧张。然而，C1神经元的急性功能丧失，以确认其在血压维持中的作用，尚未在有意识的动物中实现。此外，至少存在两个C1神经元亚群：投射到脊髓的亚群和投射到下丘脑的亚群，它们可能对血压有不同的影响，但尚未进行生理学检查。在目的1中，我提出的实验，允许C1神经元特异性急性抑制在休息和缺氧条件下，在目的2一种新的转基因方法功能解剖脊髓投射和下丘脑投射C1神经元和它们的作用，在BP控制。孤束核的二级神经元接收来自各种感觉器官的输入，并将此信息传递到整个脑干。有许多感觉输入汇聚在同一区域，这使得很难从功能上解剖这些二级神经元。外周化学反射，动脉缺氧和高碳酸血症的感觉，对于血压控制和高血压病理学特别重要。以前的实验已经能够识别负责外周化学反射的二级神经元，但是它们的投射和生理能力的全部范围仍然未知。在本提案的目标3中，我将使用一种新技术，该技术将允许对NTS的缺氧敏感神经元进行遗传靶向，以识别并功能性地确认它们的投射。

 DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States today. Hypertension is believed to account to 40% of this mortality. The central nervous system contributes to resting blood pressure, mainly through the sympathetic nervous system, and many forms of hypertension are believed to have a neurological component. How the neural circuitry of the brain controls blood pressure is incompletely understood. Generalized regions of the brain are known to be important, but the specific types of neurons involved, and what they do have been difficult to determine. The objective of the proposed research is to determine the neural circuits in the brain that are responsible for blood pressure control at the cellular level. The experiments will allow for identification and functiona characterization of unique neuronal groups involved in blood pressure control, the second-order neurons of the nucleus of the solitary tract and hypothalamus projecting C1 neurons. The design utilizes state-of-the-art transgenic techniques and physiological recording methods enabling experiments to be performed in conscious, unrestrained animals. The C1 neurons are a population of catcholaminergic neurons localized to the rostral ventrolateral medulla that have been implicated in blood pressure control for decades. Significant research has established C1 neurons are activated by numerous stressors, are likely important for the peripheral chemoreflex and may provide for resting sympathetic tone. However, acute loss-of-function of C1 neurons, to confirm their role in blood pressure maintenance, has not been achieved in conscious animals. In addition, there exist at least two subpopulations of C1 neurons; those that project to the spinal cord and those that project to the hypothalamus, which may have differential effect on blood pressure, but have yet to be examined physiologically. In Aim 1 I propose experiments that allow for C1 neuron-specific acute inhibition under resting and hypoxic conditions, and in Aim 2 a novel transgenic approach to functionally dissect spinally-projecting and hypothalamic-projecting C1 neurons and their roles in BP control. The second-order neurons of the nucleus of the solitary tract receive inputs from various sensory organs, and relay this information throughout the brainstem. There are numerous sensory inputs that converge in the same area, making it difficult to functionally dissect these second-order neurons. The peripheral chemoreflex, sensation of arterial hypoxia and hypercapnia, is particularly important for blood pressure control and hypertension pathology. Previous experiments have been able to identify second-order neurons responsible for the peripheral chemoreflex, however the full extent of their projections and physiological capabilities are still unknown. In Aim 3 of this proposal, I wil use a new technology that will allow for genetic targeting of the hypoxia-sensitive neurons of the NTS to identify and functionally confirm their projections.