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 ?m, including flow mechanics and active responses of vessel walls to hemodynamic, neural and metabolic stimuli), at the vessel scale (~100 ?m, including segment flow resistance, oxygen loss and propagation of conducted responses along vessel walls) and at the network and tissue scale (~1000 ?m, 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.

Public Health Relevance

Distribution of blood flow according to the needs of tissues, particularly for oxygen, is achieved by local regulation of blood flow, through the adjustment of diameters of small arteries and arterioles. The overall goal of this project is to gain quantitative understanding of blood flow and oxygen transport to brain tissue through the development of multiscale theoretical models. The insights gained in this project will have potential applications to normal physiology and to a range of conditions in which oxygen transport to tissue is impaired, including stroke, brain injury and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL133362-04
Application #
9981793
Study Section
Special Emphasis Panel (ZEB1)
Program Officer
Qasba, Pankaj
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
L├╝cker, Adrien; Secomb, Timothy W; Barrett, Matthew J P et al. (2018) The Relation Between Capillary Transit Times and Hemoglobin Saturation Heterogeneity. Part 2: Capillary Networks. Front Physiol 9:1296