Postnatal Development of the Neuro-Glio-Vascular Unit

描述（由申请人提供）：大脑具有特别高的能量需求，主要用于支持突触传递和动作电位传播。在没有血液流动的情况下，大脑功能在几秒钟内就会被破坏，神经元损伤在几分钟内就会发生。因此，精确地满足局部代谢需求的微血管网络是神经血管耦合机制，其已经发展为精确地将微区域血流与波动的局部氧消耗相匹配。虽然大脑的较大血管结构在胚胎阶段形成，但微血管系统（大多数氧气扩散的部位）在小鼠胚胎期结束和出生后第一个月之间发育。然而，有，有限的知识，在出生后的微血管网络的成熟和微血管，星形胶质细胞和周细胞之间的相互作用（神经血管耦合所需的过程。必需的.此外，“神经胶质血管”单位-NGVU），我们最近进行了第一次全面的体内成像研究的微血管可塑性，从出生到死亡。我们发现，新生小鼠的皮质微血管通过短距离发芽和伴随的退化发育。在关键的新生儿时期，这一过程的扰动导致微血管密度的不可逆降低，从而导致对缺氧和突触丢失的易感性。我们假设新生儿微血管网络和NGVU发育的中断导致代谢需求/供应失衡，导致终身神经功能障碍和病理学。我们将使用复杂的体内成像工具、环境和分子操作来：1）确定导致结构和功能成熟的NGVU形成的细胞相互作用的精确顺序。2)表征破坏NGVU出生后发育的细胞、分子和环境因素。3)确定异常NGVU发展的功能和结构后果。我们的研究将提高对神经血管发育机制的理解，这可能对发育障碍，神经退行性变和年龄相关的认知下降的发病机制产生影响。

DESCRIPTION (provided by applicant): The brain has exceptionally high energetic demand mainly to support synaptic transmission and action potential propagation. In the absence of blood flow, brain function is disrupted within seconds and neuronal damage occurs within minutes. Thus a microvascular network that precisely meets local metabolic demand is neurovascular coupling mechanisms have evolved to precisely match micro-regional blood flow to the fluctuating local oxygen consumption. While the larger vascular structures of the brain form during embryonic stages, the microvasculature, the site of most oxygen diffusion, develops between the end of the embryonic period and the first postnatal month in mice. There is, however, limited knowledge about the processes involved in the postnatal maturation of the microvascular network and the interactions between microvessels, astrocytes and pericytes (required for neurovascular coupling. required. Furthermore, "neuro-glio-vascular" unit -NGVU) we have recently performed the first comprehensive in vivo imaging study of microvascular plasticity from birth to death. We found, that the cortical microvasculature in neonatal mice develops through short-distance sprouting and concomitant regression. Perturbation of this process during a critical neonatal period, leads to irreversible reduction in microvascular density causing susceptibility to hypoxia and synaptic loss. We hypothesize that disruption in the neonatal development of the microvascular network and NGVU lead to metabolic demand/supply imbalance resulting in lifelong neural dysfunction and pathology. We will use sophisticated in vivo imaging tools, environmental and molecular manipulations to: 1) Determine the precise sequence of cellular interactions leading to the formation of a structurally and functionally mature NGVU. 2) Characterize cellular, molecular and environmental factors that disrupt the postnatal development of the NGVU. 3) Determine the functional and structural consequences of abnormal NGVU development. Our studies will improve understanding of mechanisms of neurovascular development that could have implications in the pathogenesis of developmental disorders, neurodegeneration and age-related cognitive decline.