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.

Public Health Relevance

The brain has exceptionally high energetic demand. In the absence of blood flow, brain function is disrupted within seconds and neuronal damage occurs within minutes. Our study will use sophisticated in vivo imaging tools, environmental and molecular manipulations to investigate cellular and molecular mechanisms involved in the development of the cerebral microvasculature. We will also study the role of astrocytes and pericytes in the structural and functional maturation of cerebral microvessels. 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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS089734-01
Application #
8801436
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510