The brain requires a vast amount of energy (around 20% of the total generated in the body) to function normally. Despite this, the brain lacks energy stores and instead uses a ?just-in-time? energy delivery system known as ?functional hyperemia?, in which local blood flow increases in response to spikes in neuronal activity. This process is underlain by a range of redundant ?neurovascular coupling? mechanisms that collectively ensure the fidelity of the blood flow response to feed activity. We have discovered that these mechanisms display a striking form of plasticity, in which chronic changes in neuronal energy requirements lead to reprogramming of these vascular signaling mechanisms to augment or dampen the local delivery of blood. We term this phenomenon vascular signaling plasticity (VSP). Importantly, VSP is disrupted in a mouse model of Alzheimer?s disease, implying that loss of this process may lead to a mismatch between energy supply and demand and impair neuronal function. Here, we propose a program of research in which we develop novel workflows for chronic imaging of VSP in awake behaving animals, followed by detailed molecular analyses of the mechanisms that underlie VSP in the same cells that we image. This work will reveal a previously unknown and unsuspected mechanism for blood flow control in the brain that is critical for neuronal health, opening a new field of research into the phenomenon of VSP. Completion of this project will deliver a range of imaging tools to enable us to image blood flow and aspects of VSP non-invasively over long periods in vivo, and our work will culminate in the development of a novel brain endothelium-specific gene therapy aimed at protecting or restoring VSP in dementia, thereby safeguarding neuronal metabolism and function.
Precise control of blood flow is essential for ensuring brain cells have enough energy (extracted from the sugar, glucose, and oxygen) to fulfill their functions. Early in the development of Alzheimer?s disease?a devastating condition affecting almost 6 million Americans?brain blood flow control is disrupted, but it is unclear how this happens. We have discovered a novel mechanism (termed ?vascular signaling plasticity?) through which neurons continuously reprogram local blood vessels to tune the amount of blood they deliver. We find that this mechanism is disrupted in a mouse model of Alzheimer?s disease, leading to mismatch between brain energy supply and demand. Therefore, we propose a program of research to develop novel tools to image the newly discovered vascular signaling plasticity and understand its mechanisms. We aim to develop a novel brain endothelial gene therapy that could ultimately be used to protect or restore vascular signaling plasticity, blood flow, and brain function in Alzheimer?s disease patients.