Postnatal Development of the Neuro-Glio-Vascular Unit

点击翻译按钮获取中文摘要

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.