Regulation of activity-dependent cerebral blood flow by astrocytes

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The brain has a high energy demand but virtually no reserve energy capacity. Therefore, it is highly dependent on constant blood and nutrient flow matched dynamically with local energy demand. This is accomplished by a process called functional hyperemia (FH). FH results from creation of molecular signals from active neurons that translate to increases in the lumen diameter of local blood supply vessels and increased blood flow. However, the molecular cell to cell signaling processes that regulate FH and its spatial coordination are poorly understood. My long-term vision is to gain a comprehensive understanding of the intercellular molecular signaling mechanisms responsible for translating neuronal energy need to coordinated local and distal changes in brain vascular lumen diameter and blood flow. We and others have contributed to a wealth of evidence that brain cells called astrocytes are capable of "listening" to synaptic neuronal activity and reacting by sending vasodilatory signals to the local vasculature to increase blood flow. The role of astrocytes in genesis and spatial conduction of FH will be an overarching focus of our short term program objectives. Short term objectives (~5 years) are to: 1.Characterize astrocyte/endothelial signaling mediated by endothelial NMDA receptors 2.Define the role of astrocytes in metabolic control of vasomotor polarity 3.Characterize the role of regional astrocytic heterogeneity in neurovascular coupling 4.Develop models to study astrocyte-endothelial coupling in human neurovascular unit (NVU) Methodologies will address all objectives in a way that ensures high-impact dissemination and attracts and develops exceptional trainees. Models include brain endothelial cell and astrocyte cultures, combined pressure myography with two-photon laser scanning microscopy (TPLSM) of penetrating arterioles in brain slices, TPLSM in awake animals, and modeling of human neurovascular coupling. These approaches will leverage innovative and physiologically integrative technologies and novel leads already produced by my group. We will produce a systematic mechanistic investigation of how astrocytes influence endothelial signaling, vasodilatory neurovascular coupling and functional hyperemia - both in focal locations of enhanced activity and in distal sites due to conducted vasodilation. FH mechanisms describe how neurons are fed according to need as a basic tenet of brain function. Our findings will thus be of broad biological and medical interest to a wide scientific audience. Our program will also illuminate neurovascular coupling mechanisms central to interpretation of functional MRI data in healthy and diseased brain. Finally, our established track record of training HQP with high-impact papers, competitive funding, awards and leading edge of methodological capabilities means our program carries tremendous potential for attraction and training of high quality personnel.