The relationship between neuronal activity, blood flow and metabolism provides the basis for the functional brain imaging techniques widely in use today. Local changes in glucose utilization, oxygen utilization, blood flow and hemoglobin oxygenation are taken as indicators of the activity of neuronal pathways during behavioral tasks or mental states. Surprisingly however, the cellular mechanisms that underlie the coupling between neuronal activity, cerebral blood flow and metabolism are poorly understood. Unlike in other tissues, a complex flow of information between neurons, astrocytes, pericytes and arteriolar smooth muscle regulates blood flow. Elucidation of the mechanisms coupling brain energy supply to energy use is essential for understanding how brain imaging data relate to neural function and for using these data to identify mechanisms of neuropsychiatric disorders such as depression, Alzheimer’s disease or schizophrenia, in which alterations in neurometabolic function are detected. These mechanisms are also of great therapeutic and economic importance because of their relevance to treating stroke and other disorders of brain blood flow.This project will investigate some of the most controversial problems in our understanding of: how the brain’s energy supply is regulated at the vascular level, how this relates to the blood flow increase underlying functional imaging signals and how individual neurons and glia control their energy supply. More specifically, we will ask: how important is control of energy supply at the capillary level, by pericytes? Which synapses control blood flow, thus generating functional imaging signals, in the cortex? How are lactate and other metabolites trafficked between neurons and astrocytes? To answer these questions, we will use a combination of mathematical modeling, in vitro experiments and to a lesser extent in vivo experiments.