According to Moore, the vasculature thus directly or indirectly (via astrocytes) influences neurons. He notes that substances in blood may modulate neuron activity. The most likely candidate, he says, is nitric oxide (NO), which easily crosses the blood–brain barrier and has been shown both in brain slices and in animal models to excite (and in some cases dampen) neuronal action. Blood vessels also affect neurons via thermal and mechanical stress. Increased blood flow can alter the local temperature in a brain region. For instance, a decrease of just one degree Celsius can lead to suppressed firing rates, in some circumstances. As a rule, blood flow changes increase the temperature in outer brain areas, while decreasing the temperature of more central regions. Pressure and volume, meanwhile, within the blood vessels can change the amount that the vessels physically impact the membranes of brain cells. If pressure or volume were to increase, a vessel could bulge, blocking receptors or ion channels and thereby causing a decrease in a neuron's electrical activity.
A change in blood flow could also trigger astrocytes to release certain hormones or neurotransmitters. "If anything is going on in the blood vessel," Moore says, "the glia (astrocytes and other nonneuronal nerve cells) is in a great position to sense it." For instance, astrocytes might secrete the excitatory neurotransmitter glutamate, which binds to neurons and allows ion exchanges that cause cells to fire.
Preliminary data from Moore's lab, involving a drug that selectively binds to receptors on blood vessels (and can open or close them), has shown neurons may become more active when blood flow increases. The M.I.T. group is now trying to develop light-activated ion channels on muscle cells, which they could then selectively control to induce changes in blood flow.
The theory "brings up something that a lot of people have been ignoring—thinking that blood vessels are tubes," says Edith Hamel, a professor of neurology at McGill University in Montreal, who believes that Moore's theory will one day prove true. "But, they are live cells…like neurons." She likens the vasculature interaction within the nervous system to that of the infrastructure of a highway system. "We have always been looking at the highway going out of the city," she says. "We need to look at the one coming into the city, as well."
Rick Buxton, a radiology professor at the University of California, San Diego, finds the idea intriguing, but he is "skeptical that blood flow is really an important modulator." In his interpretation, the rush of blood is necessary to maintain oxygen levels in the tissue, because neurons may take in oxygen at a slower rate than normal when blood is gushing by; therefore, more is needed to properly nourish the cells. Another possible way to account for the excess blood flow, according to some researchers, is that it may help carry away some of the heat generated by neuronal firing. "If there's some low level of neuromodulation in there, [as well], that's good," Buxton adds.
Moore notes that if the blood is responsible for a relatively low level of neuromodulation, it could still be significant. "Let's say that blood flow accounts for 5 percent of the variance of activity in cortical neurons," he supposes. "Five percent of the neuron's work—that's huge, if it's pushing around excitability by that scale."
Moore's theory is supported by research into neurodegenerative and mental disorders. Constantino Iadecola, a professor of neurology and neuroscience at Weill Cornell Medical College in New York City, for instance, has found a link between blood vessels and neurons in his work on Alzheimer's disease.
"We have provided evidence that the vasculature is the first thing that goes," he says, noting that Alzheimer's-associated dementia was previously split into two groups: vascular-induced (in which neurons die due to improper blood flow) and neurodegeneration-induced (with vasculature collapse following nerve cell death). "What's emerging from the literature now is that the [vessel changes occur] at least as early or earlier than the neuronal changes."