Brainstem control of blood pressure in conscious rodents

脑干对清醒啮齿动物血压的控制

基本信息

批准号：
9127736
负责人：
Ian Christopher Wenker
金额：
$ 5.61万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-30 至 2017-06-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127736
关键词：
Accounting Acute Anesthesia procedures Animals Area Blood Pressure Brain Brain Stem Brain region Breathing Cardiovascular Diseases Carotid Body Cause of Death Cells Cessation of life Chimeric Proteins Conscious Data Disease Environmental air flow Esthesia Genetic Genetic Recombination Glutamates Goals Health Hemorrhage Human Hypercapnia Hypertension Hypothalamic structure Hypoxia Kidney Maintenance Mammals Measures Methods Mus Nerve Neuraxis Neurologic Neurons Nucleus solitarius Organ Pathology Pathway interactions Peripheral Phenotype Physiological Population Population Heterogeneity Preparation Property Rattus Reflex action Regulation Research Rest Rodent Role Sensory Slice Sodium Spinal Cord Stress Sympathetic Nervous System System Techniques Testing Time Tissues Transgenic Mice Transgenic Organisms United States Viral Vector Work adeno-associated viral vector awake blood pressure regulation brain pathway design hypothalamic pituitary axis in vivo loss of function mind control mortality neural circuit new technology novel optogenetics recombinase research study sensory input stressor vector

项目摘要

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.

描述（由申请人提供）：心血管疾病是当今美国死亡的主要原因，据信高血压占该死亡率的 40%。中枢神经系统主要通过交感神经系统影响静息血压。许多形式的高血压被认为与神经系统有关。大脑的神经回路如何控制血压尚不完全清楚，但所涉及的神经元的具体类型及其作用尚不完全清楚。有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，这些实验将能够识别与血压有关的独特神经群并对其进行功能表征。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、不受约束的动物中进行。是几十年来，大量研究表明，位于延髓头侧腹外侧的一类神经元与血压控制有关，C1 神经元可被多种应激源激活，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。，C1神经元的急性功能丧失，以证实它们在维持血压中的作用，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；那些投射到脊髓的神经元和那些投射到下丘脑的神经元，可能对血压有不同的影响，但尚未进行生理学检查。在目标 1 中，我提出了允许在静息和静息状态下进行 C1 神经元特异性急性抑制的实验。在缺氧条件下，目标 2 中采用一种新的转基因方法来功能性地解剖脊髓投射和下丘脑投射 C1 神经元及其在血压控制中的作用。神经束接收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，因此很难在功能上解剖这些二阶神经元。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尤其重要，之前的实验已经能够识别负责外周化学反射的二级神经元，但其预测和生理功能的全部范围仍然未知。在该提案的第 3 部分中，我将使用一项新技术，该技术将允许对 NTS 的缺氧敏感神经元进行基因靶向，以识别并在功能上确认它们的预测。