New brain maps offer resolution finer than a millionth of a meter, reconstructed here with high microvessel density areas in red, intermediate density areas in white and low density areas in blue. Image via Xiang Ji and Edmund O’Donnell, UC San Diego

Scientists at UC San Diego may have helped answer how the brain ensures more active parts receive enough nourishment versus less demanding areas — an old neuroscience mystery, according to a study published Tuesday.

Studying the brains of mice, a team of researchers led by UCSD researchers Xiang Ji, David Kleinfeld and their colleagues deciphered the question of brain energy consumption and blood vessel density through maps detailing brain wiring to a resolution finer than a millionth of a meter — or one-hundredth of the thickness of a human hair.

A result of work at the crossroads of biology and physics, the maps provide novel insights into these “microvessels” and their various functions in blood supply chains. The techniques and technologies underlying the results are described in Tuesday’s edition of the journal Neuron.

“We developed an experimental and computational pipeline to label, image and reconstruct the microvascular system in whole mouse brains with unprecedented completeness and precision,” said Kleinfeld, a professor in UCSD’s department of physics and section of neurobiology.

Kleinfeld says the effort was akin to reverse engineering nature.

“This allowed Xiang to carry out sophisticated calculations that not just related brain energy use to vessel density, but also predicted a tipping point between the loss of brain capillaries and a sudden drop in brain health,” he said.

Questions surrounding how blood vessels carry nourishment to active and less active regions of the brain were posed as a general issue in physiology as far back as 1920. By the 1980s, a technology known as autoradiography, the predecessor of modern-day positron emission tomography, allowed scientists to measure the distribution of sugar metabolism across the mouse brain.

To fully grasp and solve the problem, Ji, Kleinfeld and their colleagues at the Howard Hughes Medical Institute’s Janelia Research Campus and UCSD Jacobs School of Engineering filled 99.9% of the vessels in the mouse brain — nearly 6.5 million vessels — with a dye-labeled gel.

They then imaged the full extent of the brain with sub-micrometer precision, which resulted in fifteen trillion voxels, or individual volumetric elements, per brain, that were transformed into a digital vascular network that could be analyzed with the tools of data science.

With their new maps in hand, the researchers determined that the concentration of oxygen is roughly the same in every region of the brain. But they found that small blood vessels are the key components that compensate for varying energy requirements.

For example, white matter tracts, which transfer nerve impulses across the two brain hemispheres and to the spinal cord, are regions of low energy needs. The researchers identified lower levels of blood vessels there.

By contrast, brain regions that coordinate the perception of sound use three times more energy and, they discovered, were found with a much greater level of blood vessel density.

“In the era of increasing complexities being unraveled in biological systems, it is fascinating to observe the emergence of shared simple and quantitative design rules underlaying the seemingly complicated networks across mammalian brains,” said Ji, a graduate student in physics.

Next, the researchers hope to drill down into the finer aspects of their new maps to determine the detailed patterns of blood flow into and out from the entire brain. They will also pursue the largely uncharted relationship between the brain and the immune system.

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