Though it accounts for just two percent of the body’s weight, the brain consumes a whopping 20% of its total energy. To get the energy it needs for more complicated tasks, the brain has evolved a system that allows it to quickly and efficiently send blood to the areas that need it most at any given moment. But how that system works has remained something of a mystery, though it is essential to healthy neural function. But that could change thanks to new research in mice from scientists at Harvard Medical School (HMS), the Broad Institute of MIT and Harvard, and Weill Cornell Medicine.
Details are available in a new Cell paper titled “Brain endothelial gap junction coupling enables rapid vasodilation propagation during neurovascular coupling.” In the paper, the scientists describe identifying specialized clusters of intercellular channels made of connexin proteins in the lining of its blood vessels that the brain uses to communicate where blood is needed.
Armed with optogenetic methods and sources of visual stimuli for the mice, they demonstrated that “endothelial connexins are critical for relaying the signals sensed by the microvasculature to distal upstream arteries acute coupling of blood flow to neural activity,” according to the paper. Furthermore, “acute, arterial endothelial cell type-specific deletion” of two connexins—Cx37 and Cx40—“abolishes arterial gap junction coupling and results in impaired vasodilation” of the blood vessels.
“There’s an elegant evolutionary mechanism that [is] distributing blood flow on demand throughout the brain, but we don’t understand how it works,” said Trevor Krolak, co-lead author on the study and a doctoral student at HMS. The findings reported in Cell “help us understand how you can get that super-important blood supply to the correct areas of the brain on a time scale that is useful,” added Luke Kaplan, PhD, co-lead author on the paper and a neurobiology research fellow at HMS.
And there are potential benefits if their findings are further confirmed in other model animals and human studies. For example, scientists could study how this blood allocation process deteriorates in neurodegenerative disease cases, potentially opening a door to new therapies for diseases of the central nervous system (CNS).
To understand what happens on a molecular level as different brain regions increase their activity, the scientists ran a series of experiments in mice. Their analysis showed that the brain rapidly signals that a particular area needs more blood by using the endothelial cells that line the blood vessels in the brain. Through this “coordinated signaling highway,” the brain can communicate which blood vessels need to dilate or contract at the same time to move blood where it needs to go.
Furthermore, because brain vasculature is highly conserved in mammals, the same system likely operates in humans. Besides new insights into neurodegeneration, if the findings translate to humans, the researchers also see a possible benefit for the interpretation of fMRI scans, which rely on the link between blood flow and neural activity. “Now that we’ve figured out the mechanism, we want to apply our knowledge to understanding disease and developing therapies,” said Chenghua Gu, PhD, senior author on the study and a professor of neurobiology at HMS.
Though this study focuses on the brain, its implications go beyond diseases of the CNS. Other types of cells in the body are connected by gap junctions, and previous studies have implicated mutations in gap junction genes in heart conditions, deafness, and other diseases. Studies like this could provide a foundation for future research into how cells throughout the body use these kinds of connections to communicate.
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