Brainstem Control of Cerebral Blood Flow in Traumatic Subarachnoid Hemorrhage

脑干对创伤性蛛网膜下腔出血脑血流的控制

• 批准号: 9174068
• 负责人: JUSTIN S. CETAS
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174068
• 关键词: Acute; Address; Arteries; Attention; Autologous; Blast Injuries; Blood; Brain Stem; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Chronic; Data; Defect; Endothelium; Event; Failure; Functional disorder; Image; Impaired cognition; Inflammation; Injectable; Injury; Ischemia; Lasers; Learning; Magnetic Resonance Imaging; Maintenance; Measures; Medial; Mediating; Mediator of activation protein; Medulla Oblongata; Morbidity - disease rate; Nerve; Neural Pathways; Neuraxis; Neurocognitive; Neuronal Injury; Neurons; Optics; Outcome; Pathogenesis; Pathway interactions; Patients; Perfusion; Pharmacology; Physiological; Physiology; Play; Population; Regulation; Rest; Rodent Model; Role; Rotarod Performance Test; Sensory; Smooth Muscle; Subarachnoid Hemorrhage; Techniques; Testing; Traumatic Brain Injury; Traumatic Subarachnoid Hemorrhage; Trigeminal System; Vasospasm; behavioral study; cognitive change; extracellular; microangiography; morris water maze; mortality; nerve supply; neural circuit; neurochemistry; neurophysiology; neurovascular; novel; prevent; public health relevance; response; restoration; tool

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage (SAH) resulting from traumatic brain injury (TBI) can cause vasospasm, defects in cerebral blood flow (CBF) and cognitive decline. Traumatic SAH is associated with poor outcomes. The underlying causes for these injuries are unknown. Parasympathetic efferents and trigeminal afferents innervating large cerebral vessels as well as intrinsic innervation of cortical vessels may play a role in regulating CBF after injury. The present project focuses on a central neural circuit that has the potential to regulate neurovascular interactions by modulating the perivascular innervation. The objective of the proposed study is to explore a novel hypothesis, namely that the brainstem is an important mediator of cerebral perfusion during SAH. More specifically, an important medullary autonomic and sensorimotor integration center, the rostroventral medial medulla (RVM) modulates cerebral blood flow as part of a coordinated response to SAH aimed at preventing ischemia, and that failure of brainstem compensatory mechanisms contributes to the pathophysiology of subarachnoid hemorrhage. We will test three specific aims. 1. The specific neural pathways through which the RVM modulates CBF (Cetas et al., 2009) are unknown. We will test the role of parasympathetic and sympathetic outflows, interactions with trigeminal sensory pathways, and connections within the central nervous system in the effects of RVM stimulation. 2. The neurons in the RVM are diverse in terms of neurochemistry, physiology, and pharmacology. We will determine which of the physiologically defined RVM cell classes respond to SAH, and test the hypothesis that a class of neurons known to be activated by dural inflammation, "ON-cells," are critical for an acute compensatory response that contributes to the restoration of CBF following an experimental SAH. 3. Determine the role of the RVM in delayed cerebral ischemia after experimental subarachnoid hemorrhage. Our overarching hypothesis in this Aim is that a failure or reorganization of RVM modulatory mechanisms is important in delayed ischemia following SAH. We will use pharmacological tools to manipulate functionally specific RVM neuronal populations. Effects of RVM manipulation on long-term outcomes will be assessed with quantitative MRI imaging and neurocognitive behavioral studies. This will allow us to test whether distinct neuronal groups in the RVM have an ongoing role in regulation of CBF in the chronic timeframe following experimental SAH. We have adapted a rodent model of SAH in which autologous blood is injected into the prechiasmatic cistern. CBF will be measured using laser Doppler and the powerful optical microangiography (OMAG). MRI will be used to supplement OMAG and correlate changes in CBF with regional isechemia and neuronal injury. We will use pharmacological tools to manipulate functionally specific RVM neuronal populations. Particular classes of RVM neurons will be indentified using standard extracellular neurophysiological recording techniques. Cognitive changes will be tested using standard learning paradigms such as the rotarod test and modified Morris water maze.

描述（由申请人提供）： 由创伤性脑损伤（TBI）引起的亚蛛网膜下腔出血（SAH）会导致血管痉挛，脑血流缺陷（CBF）和认知能力下降。创伤性SAH与结果不佳有关。这些伤害的根本原因尚不清楚。副交感神经传出和三叉神经支配的大脑血管以及皮质血管的内在神经支配可能在受伤后调节CBF方面发挥作用。本项目的重点是中央神经回路，该电路具有通过调节血管周神经来调节神经血管相互作用的潜力。拟议的研究的目的是探索一种新的假设，即脑干是SAH期间脑灌注的重要介体。更具体地说，一个重要的髓质自主神经和感觉运动整合中心，延髓髓质髓质（RVM）调节脑血流，这是对旨在预防局部缺血的协调反应的一部分，旨在预防脑干补偿机制的失败会导致subararachnoid Hemorhage subararachnoid Hemorhage的病理学病学。我们将测试三个具体目标。 1。RVM调节CBF的特定神经途径（Cetas等，2009）是未知的。我们将测试副交感神经和交感神经流出的作用，与三叉神经感觉途径的相互作用以及中枢神经系统内的连接在RVM刺激的影响中。 2。RVM中的神经元在神经化学，生理学和药理学方面是多种多样的。我们将确定哪些生理定义的RVM细胞类对SAH有反应，并检验以下假设：一类已知的神经元被硬脑膜炎症激活，“网络元素”至关重要，这对于急性补偿性反应至关重要，这对实验性SAH经过实验性SAH的恢复有助于恢复CBF。 3。确定实验性蛛网膜下腔出血后RVM在延迟脑缺血中的作用。我们在此目标中的总体假设是，RVM调节机制的失败或重组对于SAH后的延迟缺血很重要。我们将使用药理学工具来操纵功能特定的RVM神经元种群。 RVM操纵对长期结局的影响将通过定量MRI成像和神经认知行为研究来评估。这将使我们能够测试RVM中不同的神经元组在实验SAH后的慢性时框架中的CBF调节中是否具有持续的作用。我们已经改编了一种SAH的啮齿动物模型，其中自体血被注入术前的水箱中。 CBF将使用激光多普勒和强大的光学微型摄影（OMAG）测量。 MRI将用于补充OMAG，并将CBF的变化与区域性感血肿和神经元损伤相关。我们将使用药理学工具来操纵功能特定的RVM神经元种群。使用标准的细胞外神经生理记录技术将缩进特定类别的RVM神经元。认知变化将使用标准学习范式（例如Rotarod检验和修改的Morris Water Maze）进行测试。