SUMMARY Neuronal activity leads to increases in local cerebral blood flow (CBF) to allow adequate supply of O2 and nutrients to active neurons. This process, termed neurovascular coupling (NVC), is essential for survival and its disruption is associated with cognitive decline and dementia. Despite significant findings, we are still far from reaching a comprehensive understanding of NVC. This prohibits us from a thorough understanding of normal brain function and from identifying critical failures in disease and hinders investigations into the vascular origins of cognitive impairment. The objective of this application is to investigate how K+-mediated local CBF control emerges from the integration of neuronal inputs and autoregulatory feedback. This will be accomplished by pursuing two specific aims: In Aim 1, models of endothelial and smooth muscle cells will be developed and examine K+-mediated electrical signaling in capillaries and arterioles. We propose that the inward rectifying K+ channel acts as bistable, “on-off”, switch to hyperpolarize cell membranes when extracellular K+ increases. Multi- cellular models of microvascular networks will examine communication between capillaries and their feeding arteriole, and the significance of capillary-level NVC for local CBF control. We propose that regenerative signal propagation enables this communication and we will test this hypothesis using modeling and an ex-vivo intact arteriole-capillary preparation. In Aim 2, simulations in a geometrically accurate vascular network will predict macroscopic changes in blood flow following functional activation. We will integrate theory and experiments to analyze channelopathy-like defects, in animal models of cerebral small vessel and Alzheimer's disease. We will test the hypothesis that impaired capillary-arteriole communication and altered myogenic response lead to a NVC deficit and propose optimal strategies for restoring this deficit. The proposed work will provide a paradigm for comprehensive examinations of cerebral blood flow control, for interpreting altered cellular signaling in disease and for elucidating vascular underpinnings in cognitive impairment.