Postnatal Development of the Neuro-Glio-Vascular Unit

描述(申请人提供)：大脑有非常高的能量需求，主要是支持突触传递和动作电位传播。在没有血流的情况下，大脑功能在几秒钟内就会中断，神经元损伤会在几分钟内发生。因此，一个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，它已经进化成精确地匹配微区域血流和波动的局部耗氧量。虽然大脑中较大的血管结构是在胚胎阶段形成的，但在小鼠中，微血管系统是氧气扩散最多的地方，在胚胎末期和出生后第一个月之间发展。然而，关于微血管网络的后天成熟过程以及微血管、星形胶质细胞和周细胞之间的相互作用(神经血管偶联所需)的知识有限。必填项。此外，我们最近还对从出生到死亡的微血管可塑性进行了第一次全面的活体成像研究。我们发现，新生小鼠的皮质微血管是通过短距离萌发和伴随的退化而发育的。在关键的新生儿时期，这一过程的扰动会导致微血管密度不可逆转地减少，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的发育中断会导致代谢需求/供应失衡，从而导致终生神经功能障碍和病理。我们将使用先进的活体成像工具、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序列。2)确定干扰NGVU出生后发育的细胞、分子和环境因素。3)确定NGVU发展异常的功能和结构后果。我们的研究将提高对神经血管发育机制的理解，这些机制可能在发育障碍、神经退行性疾病和年龄相关性认知下降的发病机制中具有意义。

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.