The mechanisms and role of postnatal cerebral vascular remodeling

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DESCRIPTION (provided by applicant): Cerebral blood flow is tightly regulated to meet the brain's large energetic needs. Yet it remains unclear how a precise matching between the degree of vascularization and regional metabolic demands is achieved during development. The brain's energetic needs increase dramatically in the early postnatal period due to massive synaptogenesis. However, the process of postnatal vascular remodeling, which could be critical for establishing an adequate vascular network, remains poorly understood. This proposal aims at increasing our understanding of postnatal vascular remodeling. We hypothesize that neuronal activity promotes postnatal vascular remodeling via vascular endothelial growth factor (VEGF) and that transient disruption of this process has permanent consequences on neuronal connectivity. To test this, we will use a variety of genetic and pharmacological methods to alter neuronal activity as well as vascular and neuronal imaging in fixed tissues and the living mouse brain using two-photon microscopy. In specific aim 1, we characterize the patterns of vascular remodeling by measuring the degree of angiogenesis, sprouting and pruning and correlate it with regional synaptic density. In aim 2, we determine the effects of neuronal activity on vascular remodeling by altering neuronal activity using pharmacological and genetic methods. We also measure the effect of neuronal activity on levels of VEGF. In aim 3, we determine the effects of altering postnatal vascular remodeling on neuronal structure and connectivity. Additionally, we test whether vascular remodeling occurs within a critical period analogous to that observed with postnatal refinement of neuronal connections. Together, these studies will greatly advance our understanding of the mechanisms of postnatal vascular remodeling which may be critically important in meeting the metabolic demands of the brain and maintaining the health of neurons.