The brain is a thirsty organ. Neuroscientists at Harvard Medical School discovered a control mechanism in the brains of mice that regulates proper blood flow to areas of greater neural activity, in a rapid-response, precise reaction.
A link between the hearts and minds of mouse brains
The scientists' experiments show how arteries in the brain actively regulate neurovascular coupling in response to neural activity, and also how the protein called Mfsd2a — previously shown to be a key regulator of the thin but crucial protective blood-brain barrier — is a critical part of this neurovascular coupling process.
The experiments' findings reveal how these mechanisms open new directions in the study of neurovascular coupling in neurological diseases.
"We now have a firm handle on the mechanisms involved in neurovascular coupling, including its molecular, cellular and subcellular components, which we've never had before," said Chenghua Gu, lead author of the study and professor of neurobiology in the Blavatnik Institute at Harvard Medical School (HMS) and a Howard Hughes Medical Institute faculty scholar.
"This puts us in a position to dissect this process and determine, for example, whether the neurovascular coupling impairments that we see in diseases like Alzheimer's are the result of a pathology or the cause," said Gu.
Tickled whiskers change the blood flow in brains
Earlier studies saw Gu and colleagues demonstrate how the protective integrity of the blood-brain barrier is secured by the protein Mfsd2a, which works to suppress the formation of caveolae — small lipid bubbles that hold signaling molecules — for capillaries inside mice brains.
Much to their surprise, the team found that arteries — blood vessels that carry nutrient-saturated blood up from the lungs and constitute roughly 5% of the total blood vessels in the brain — had opposite characteristics of the capillaries. Arteries with a scarcity of Mfsd2a showed high levels of caveolae.
The latest findings were made via observation. In addition to Gu, co-first authors Vicente Nunez and Brian Chow, HMS research fellows in neurobiology, the researchers stimulated the whiskers of healthy, awake mice while at the same time live-imaging the animals' brain activity via a powerful method called 2-photon microscopy.
While fumbling whiskers, normal mice exhibited higher neural activity, blood flow and arterial diameter in the corresponding area of the brain dedicated to sense perception. But a group of mice who were genetically engineered to lack caveolae showed the same neural event, with however lower blood flow and arterial dilation, which suggests a deficit in neurovascular coupling.
The team forced endothelial cells — which compose the lining of arteries — to mimic the activity of ones with the normally-lacking Mfsd2a by blocking the cells from forming caveolae. This significantly impaired neurovascular coupling, which shows how important caveolae are in the arteries.
There is much more to the study than is covered here, but a key takeaway from this groundbreaking discovery of the mechanistic structure underlying neurovascular coupling is that every neurological disease caused by irregularities of blood flow to the brain — like Alzheimer's, dementia, and many, many others — may one day be healed thanks in part to these scientists.