Endothelial Gap Junctions in the Control of Neurovascular Coupling

Abstract

The brain depends on a highly regulated blood supply to power the energetically expensive computations that underlie cognition. To ensure that energetic resources are efficiently allocated, the brain dynamically redistributes blood flow to active regions via a process known as neurovascular coupling. This close matching of neural activity and hemodynamics is thought to be essential for neuronal homeostasis and forms the basis of non-invasive functional brain imaging in humans. That said, the molecular mechanisms underlying neurovascular coupling remain poorly understood. To generate robust changes in local perfusion, neurovascular coupling involves the rapid, coordinated dilation of large stretches of the brain’s arterial network. The goal of this dissertation is to understand how this finely tuned, moment-to-moment matching of neuronal and vascular systems is achieved. Specifically, we demonstrate that endothelial gap junction-mediated signaling serves as an intermediary linking neuronal activation to long-range mobilization of the arterial network. Leveraging a novel, endothelial-specific adeno-associated virus variant, we develop a non-invasive methodology to assay gap junction coupling in vivo. Using this technique, we find that endothelial cells throughout the central nervous system are functionally interconnected by gap junctions. Furthermore, we find that both the strength of this coupling and the specific connexin isoforms used by endothelial cells to form gap junctions vary along the arterio-venous axis. Based on these results, we generate a conditional loss-of-function mouse model to acutely abolish arterial endothelial cell gap junction coupling in the cerebrovasculature. Finally, using a combination of visual and optogenetic stimuli presented to awake mice, we show that endothelial gap junction coupling is essential for rapid, long-range propagation of vasodilation during neurovascular coupling.