Mechanisms of neurovascular coupling in humans

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Background: The brain requires precise control of blood flow to ensure that appropriate energy is provided and waste is removed. The need for exceptionally controlled regulation in the brain is primarily due to the limited capacity for energy storage and high metabolic demand in this tissue. Neurovascular coupling (NVC) is thought to be a key mechanism regulating this control and describes the close temporal and regional linkage between neuronal activity and cerebral blood flow (CBF) responses. The neurovascular unit is well-equipped to control blood flow precisely, which is accomplished by the close interaction of three major components: 1) Vascular contractile cells; 2) The endothelium; 3) The neuron; and 4) The astrocyte.******Importance: Unraveling the mechanisms of NVC is important to understanding fundamental central nervous system processes such as thought itself and how cognition changes over the human lifespan. ******Rationale: Much of the research into the mechanisms of NVC has been completed using animal models with anesthesia that impacts CBF regulation, or ex vivo models where important inputs to NVC may be disconnected (e.g., central sympathetic nervous system input). Furthermore, interspecies differences, particularly in terms of brain function, have been uncovered. These issues obviate clear understanding of NVC. Nonetheless, animal work shows that important components of the NVC cascade may be: 1) Nitric oxide production (a potent vasoactive substance) through nitric oxide synthase (NOS); and 2) Specific cell receptors (alpha1 and beta). These findings in animals form the starting point for my NVC research program using an in vivo un-anesthetized human model. ******Overall Goals: A) To advance our knowledge of NVC using novel interventions and research approaches, B) Produce technology improving the ease/quality of NVC assessments (e.g., novel software/hardware); C) Train the next generation of natural science/engineering HQP. ******Discovery Themes: 1) Delineate the role of NOS in NVC; 2) Understand the impact of alpha1 adrenergic receptors inNVC; 3) Reveal the influence of beta adrenergic receptors in NVC.******Nature of Work: Using pharmacological and dietary interventions we will systematically inhibit and promote the NOS, alpha1 and beta pathways in 24 humans and evaluate the impact of these pathways on NVC. This will require 15 studies (312 assessments), taking place over 5 years.