NSF Award
0002945
0002945<br/>Hudetz<br/>The goal of this proposal is to determine if the distribution of red blood cell (RBC) flow in the cerebral cortical capillary network is altered during functional activation of the brain cortex and if nitric oxide (NO) from neuronal NO synthase participates in this response. The investigator hypothesis is that a change in distribution of RBC flow rates toward a more homogeneous perfusion in the capillary network occurs during neuronal activation and is significant for the maintenance of tissue oxygen supply. The investigator further hypothesize that nitric oxide (NO) from neuronal (Type I) NOS is critically involved in RBC flow regulation at the single capillary level. These hypotheses will be tested using a cross-disciplinary approach. Experiments will be performed by direct observation of the cerebral cortical capillary circulation in vivo using fluorescence video-microscopy in rodents. RBC velocity, RBC supply rate (RBC flux) will be measured from sequential video images. Three-dimensional architecture of the capillary network will be reconstructed using computer software developed in the investigator's laboratory. Neuronal activation will be performed by physiological stimulation of the whisker barrel cortex and by transcranial electrical stimulation. Changes in distribution of RBC perfusion in the capillary network upon neuronal activation will be assessed. The postulated role of neuronal NO in the regulation of intranetwork RBC flow distribution will be tested using models with pharmacological inhibition of NO synthase (NOS) systems, NO donors and in mice with targeted disruption of the neuronal NOS (nNOS) gene. Mathematical modeling of oxygen transport from capillary segments based on measured RBC flow data will be performed to estimate the significance of capillary flow distribution changes for O2 transport during functional activation. These studies will advance our knowledge of the fundamental cellular mechanism of neuronal activity-blood flow coupling at the microvascular level which is essential to better understand both normal neurobiology and the underlying mechanism of functional brain imaging.
