Understanding cellular architecture of the neurovascular unit and its function in the whole mouse brain

了解神经血管单元的细胞结构及其在整个小鼠大脑中的功能

• 批准号: 9767300
• 负责人: Yongsoo Kim
• 金额: $ 60.05万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767300
• 关键词: 3-Dimensional; Active Sites; Affect; Aging; Albumins; Alzheimer' s Disease; Anatomy; Animals; Architecture; Area; Atherosclerosis; Blood Vessels; Brain; Brain Diseases; Brain Mapping; Brain region; Caliber; Cells; Cerebrum; Communities; Complex; Data; Data Set; Environment; Female; Fluorescein; Foundations; Gel; Genetic; Goals; Health; Heterogeneity; Homeostasis; Image; Imagery; Impaired cognition; Infrastructure; Infusion procedures; Injury; Internet; Interneurons; Label; Lead; Link; Maps; Mediating; Metabolic; Methods; Microanatomy; Modeling; Mus; Neocortex; Neuroglia; Neurologic; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Nutrient; Online Systems; Oxygen; Parvalbumins; Pathologic; Pathology; Pericytes; Physiological; Play; Regulation; Reporter; Research Personnel; Resolution; Resources; Role; Sensory; Signaling Molecule; Smooth Muscle Myocytes; Specificity; Stroke; Structure; Surface; Symptoms; System; Trees; Vascular blood supply; Vasoactive Intestinal Peptide; Vasodilation; Vasomotor; Vibrissae; Whole Organism; Work; age related; aged; awake; base; blood perfusion; brain health; cell motility; cell type; cerebral microvasculature; cognitive function; computerized tools; excitatory neuron; human disease; in vivo; in vivo calcium imaging; innovation; insight; male; nervous system disorder; neural circuit; neuropathology; neuropeptide Y; neurovascular; neurovascular coupling; neurovascular unit; new technology; novel; optogenetics; relating to nervous system; response; skills; somatosensory; submicron; tomography; tool; two-photon; wasting

ABSTRACT An intricate web of blood vessels in the mammalian brain provides essential oxygen and nutrients to power the energy demands of the brain. The structure of the brain’s microvasculature provides the extraordinary surface needed for a high level of energy exchange and clearance of metabolic wastes. Small vessel pathologies are involved in cognitive decline associated with aging and many brain disorders. Mounting evidence supports the idea that neuronal activity dynamically regulates diameter of small vessels to maintain energy homeostasis. For example, when mice use their whiskers to sense the external environment, neural activity in corresponding somatosensory areas increases and small vessels in the area dilate to increase blood perfusion. Cortical interneurons, especially neuronal nitric oxide synthase (nNOS) expressing neurons, are the major cell type to mediate such neurovascular coupling. Interestingly, emerging evidence suggests that 3D distribution and function of small vessels, and their interaction with vasomotor neurons are heterogeneous in different brain regions. Moreover, some brain regions are more susceptible than others to age related degeneration, which can be linked to many neurological conditions with brain region specific symptoms such as Alzheimer's disease. To understand the underlying neurovascular mechanisms affected in health and pathological conditions, we propose to create a precise 3D map of micro vessels and cell types controlling vessel motility in the entire mammalian brain using the mouse as a model. Furthermore, we aim to gain a comprehensive understanding of neurovascular changes during aging. Towards this goal, we have created a synergistic collaborative team with complementary skill sets to establish high-resolution whole mouse brain anatomical maps of micro vessels and nNOS interneurons subtypes (Dr. Kim), to establish a web-visualization to widely disseminate these maps (Dr. Cheng), and to study functional relationships involved in the regulation of vasomotility from awake animals (Dr. Drew). The proposed work will establish reference maps that are needed as a foundation for the further study of neurovascular architectures supporting normal cognitive function and their changes in various neuropathologies.

摘要 哺乳动物大脑中错综复杂的血管网提供了必需的氧气和营养物质， 大脑的能量需求。大脑的微血管结构提供了 需要高水平的能量交换和代谢废物的清除。小血管病变是 与衰老和许多脑部疾病相关的认知能力下降有关。越来越多的证据支持 神经元活动动态调节小血管直径以维持能量稳态的观点。 例如，当老鼠用胡须感知外部环境时， 躯体感觉区域增加，并且该区域中的小血管扩张以增加血液灌注。皮质 中间神经元，特别是表达神经元型一氧化氮合酶（nNOS）的神经元，是主要的细胞类型， 介导这种神经血管耦合。有趣的是，新出现的证据表明，3D分布和 小血管的功能，以及它们与血管神经元的相互作用在不同的脑中是异质的 地区此外，某些大脑区域比其他区域更容易受到与年龄相关的退化的影响， 可能与许多具有脑区特异性症状的神经系统疾病有关，如阿尔茨海默氏症 疾病了解在健康和病理状态下受影响的神经血管机制 在这种条件下，我们建议创建一个精确的微血管和控制血管运动的细胞类型的3D地图， 整个哺乳动物的大脑，以老鼠为模型。此外，我们的目标是获得全面的 了解衰老过程中神经血管的变化。为了实现这一目标，我们创造了一个协同 具有互补技能的协作团队，以建立高分辨率的整个小鼠大脑解剖结构 微血管和nNOS中间神经元亚型的地图（Kim博士），以建立一个网络可视化， 传播这些地图（郑博士），并研究涉及调节的功能关系， 清醒动物的血管运动（Dr. Drew）。拟议的工作将建立所需的参考地图， 作为进一步研究支持正常认知功能的神经血管结构的基础， 它们在各种神经病理学上的变化。