Brainstem control of blood pressure in conscious rodents

 描述(申请人提供)：心血管疾病是当今美国的主要死亡原因。高血压被认为占死亡人数的40%。中枢神经系统主要通过交感神经系统对静息血压做出贡献，许多形式的高血压被认为有神经成分。大脑的神经回路是如何控制血压的，目前还不完全清楚。众所周知，大脑的广义区域很重要，但涉及的具体神经元类型及其作用一直很难确定。这项拟议的研究的目的是确定大脑中负责在细胞水平上控制血压的神经回路。这些实验将能够识别和描述参与血压控制的独特神经元群、孤束核的二级神经元和下丘脑投射的C1神经元。该设计利用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、无拘无束的动物身上进行。C1神经元是一群位于延髓头端腹外侧的儿胆胺能神经元，几十年来一直与血压控制有关。大量研究已经证实，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张力。然而，在清醒的动物身上还没有实现急性的C1神经元功能丧失，以证实它们在维持血压中的作用。此外，至少存在两个亚群的C1神经元；那些投射到脊髓的神经元和那些投射到下丘脑的神经元，它们可能对血压有不同的影响，但尚未进行生理检查。在目标1中，我提出了允许在静止和低氧条件下对C1神经元进行特异性急性抑制的实验，在目标2中，我提出了一种新的转基因方法来从功能上解剖脊髓投射和下丘脑投射的C1神经元及其在血压控制中的作用。孤束核的二级神经元接受来自各种感觉器官的输入，并将这些信息传递到整个脑干。有许多感觉输入汇聚在同一区域，这使得从功能上解剖这些二级神经元变得困难。外周化学反射，即动脉缺氧和高二氧化碳的感觉，对血压控制和高血压病理特别重要。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，然而它们的投射和生理功能的全面程度仍然未知。在这项提案的目标3中，我将使用一种新技术，允许对NTS的低氧敏感神经元进行基因靶向，以识别并从功能上确认它们的投射。

 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.