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

摘要 哺乳动物大脑中错综复杂的血管网络提供必要的氧气和营养物质，为 大脑的能量需求。大脑微血管的结构提供了非凡的表面 高水平的能量交换和代谢废物的清除所需的。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。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平衡的想法。 例如，当小鼠使用它们的胡须来感知外部环境时，相应的神经活动 躯体感觉区域增加，该区域的小血管扩张以增加血液灌注量。大脑皮层 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。 调节这种神经血管偶联。有趣的是，新出现的证据表明，3D分布和 小血管的功能及其与血管运动神经元的相互作用在不同的大脑中是不同的 地区。此外，大脑的某些区域比其他区域更容易发生与年龄相关的退化，这 可能与许多神经疾病有关，具有大脑区域特有的症状，如阿尔茨海默氏症 疾病。了解影响健康和病理的潜在神经血管机制 条件下，我们建议创建控制血管运动的微血管和细胞类型的精确3D图 整个哺乳动物的大脑以小鼠为模型。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 技能互补的协作团队建立高分辨率全脑解剖 微血管和nNOS中间神经元亚型图(Kim博士)，以建立一个广泛的网络可视化 传播这些地图(程博士)，并研究参与调控的功能关系 清醒动物的血管运动(德鲁博士)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构筑的基础 它们在各种神经病理中的变化。

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.