The overall goal of this proposal is to gain quantitative understanding of the relationship betweenneural activation blood flow and tissue oxygenation in the brain cortex using multiscale theoreticalmodels for blood flow oxygen transport and flow regulation in networks of microvessels. Adequateblood flow to meet spatially and temporally varying demands of brain tissue is crucial since lack of oxygenquickly 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 flowand oxygen transport are difficult to unravel and cannot be understood just by observing behavior of individualblood vessels. In the proposed work the detailed structure of microvessel networks with thousands ofsegments in the mouse cerebral cortex will be imaged using two-photon microscopy. Observations usingphosphorescence quenching nanoprobes will yield high resolution maps of tissue oxygen levels. Spectraldomain optical coherence tomography will be used to measure blood flows. The multiscale modeling approachsimulates biological and physical processes at the capillary diameter and cellular scale (~10 m including flowmechanics and active responses of vessel walls to hemodynamic neural and metabolic stimuli) at the vesselscale (~100 m including segment flow resistance oxygen loss and propagation of conducted responsesalong vessel walls) and at the network and tissue scale (~1000 m including entire network flows perfusionoxygen extraction and tissue hypoxic fraction). Specific Aim 1 is to develop predictive multiscale modelsfor blood flow and oxygen transport in the mouse cerebral cortex and validate these models usingexperimental data derived from multimodal imaging of the cortex microvasculature. The proposedstudies will provide a model that will reconcile available data at the microscopic level with macroscopic levelvariables such as perfusion and oxygen extraction and will allow prediction of tissue oxygenation andoccurrence of hypoxia for a range of blood perfusion and oxygen demand. Specific Aim 2 is to developmultiscale models for blood flow autoregulation and neurovascular coupling in the mouse cerebralcortex and to test and refine these models using experimental data derived from multimodal imagingof the cortical microvasculature. The models will include effects of myogenic metabolic shear-dependentand conducted responses as well as the possible role of capillary-level regulation. Models including orexcluding these mechanisms will be tested for their ability to represent actual regulatory responses asreported in the literature and as observed in multimodal imaging experiments under varying physiologicalconditions. Improved understanding of the mechanisms of flow regulation could lead to improved strategies fordisorders related to neurovascular function including stroke and neurodegenerative diseases and forinterpreting fMRI brain imaging.