The overall goal of this proposal is to gain quantitative understanding of the relationship between
neural activation, blood flow and tissue oxygenation in the brain cortex, using multiscale theoretical
models for blood flow, oxygen transport and flow regulation in networks of microvessels. Adequate
blood flow to meet spatially and temporally varying demands of brain tissue is crucial, since lack of oxygen
quickly leads to irreversible damage. The mechanisms by which blood flow is controlled are poorly understood.
Multiple interactions between neural activity, metabolite levels, changes in vascular tone, network blood flow,
and oxygen transport are difficult to unravel, and cannot be understood just by observing behavior of individual
blood vessels. In the proposed work, the detailed structure of microvessel networks with thousands of
segments in the mouse cerebral cortex will be imaged using two-photon microscopy. Observations using
phosphorescence quenching nanoprobes will yield high resolution maps of tissue oxygen levels. Spectral
domain optical coherence tomography will be used to measure blood flows. The multiscale modeling approach
simulates biological and physical processes at the capillary diameter and cellular scale (~10 µm, including flow
mechanics and active responses of vessel walls to hemodynamic, neural and metabolic stimuli), at the vessel
scale (~100 µm, including segment flow resistance, oxygen loss and propagation of conducted responses
along vessel walls) and at the network and tissue scale (~1000 µm, including entire network flows, perfusion,
oxygen extraction and tissue hypoxic fraction). Specific Aim 1 is to develop predictive multiscale models
for blood flow and oxygen transport in the mouse cerebral cortex, and validate these models using
experimental data derived from multimodal imaging of the cortex microvasculature. The proposed
studies will provide a model that will reconcile available data at the microscopic level with macroscopic level
variables such as perfusion and oxygen extraction and will allow prediction of tissue oxygenation and
occurrence of hypoxia for a range of blood perfusion and oxygen demand. Specific Aim 2 is to develop
multiscale models for blood flow autoregulation and neurovascular coupling in the mouse cerebral
cortex, and to test and refine these models using experimental data derived from multimodal imaging
of the cortical microvasculature. The models will include effects of myogenic, metabolic, shear-dependent
and conducted responses, as well as the possible role of capillary-level regulation. Models including or
excluding these mechanisms will be tested for their ability to represent actual regulatory responses, as
reported in the literature and as observed in multimodal imaging experiments under varying physiological
conditions. Improved understanding of the mechanisms of flow regulation could lead to improved strategies for
disorders related to neurovascular function, including stroke and neurodegenerative diseases, and for
interpreting fMRI brain imaging.