Understanding cellular architecture of the neurovascular unit and its function in the whole mouse brain

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ABSTRACT An intricate web of blood vessels in the mammalian brain provides essential oxygen and nutrients to power the energy demands of the brain. The structure of the brain’s microvasculature provides the extraordinary surface needed for a high level of energy exchange and clearance of metabolic wastes. Small vessel pathologies are involved in cognitive decline associated with aging and many brain disorders. Mounting evidence supports the idea that neuronal activity dynamically regulates diameter of small vessels to maintain energy homeostasis. For example, when mice use their whiskers to sense the external environment, neural activity in corresponding somatosensory areas increases and small vessels in the area dilate to increase blood perfusion. Cortical interneurons, especially neuronal nitric oxide synthase (nNOS) expressing neurons, are the major cell type to mediate such neurovascular coupling. Interestingly, emerging evidence suggests that 3D distribution and function of small vessels, and their interaction with vasomotor neurons are heterogeneous in different brain regions. Moreover, some brain regions are more susceptible than others to age related degeneration, which can be linked to many neurological conditions with brain region specific symptoms such as Alzheimer's disease. To understand the underlying neurovascular mechanisms affected in health and pathological conditions, we propose to create a precise 3D map of micro vessels and cell types controlling vessel motility in the entire mammalian brain using the mouse as a model. Furthermore, we aim to gain a comprehensive understanding of neurovascular changes during aging. Towards this goal, we have created a synergistic collaborative team with complementary skill sets to establish high-resolution whole mouse brain anatomical maps of micro vessels and nNOS interneurons subtypes (Dr. Kim), to establish a web-visualization to widely disseminate these maps (Dr. Cheng), and to study functional relationships involved in the regulation of vasomotility from awake animals (Dr. Drew). The proposed work will establish reference maps that are needed as a foundation for the further study of neurovascular architectures supporting normal cognitive function and their changes in various neuropathologies.