New method finally enables researchers to study oxygen in the brain

Tech Science 9. jun 2024 4 min Professor Maiken Nedergaard Written by Kristian Sjøgren

Supplying the brain with oxygen is probably the most important requirement for survival. Nevertheless, researchers have had great difficulty in measuring the distribution of oxygen in the brain. A new method, which could revolutionise brain research, shows that not being physically active is very harmful for the brain.

The brain needs oxygen, and if it is lacking, even briefly, people lose consciousness and then die.

Although researchers have known about how important oxygen is to the brain for centuries, they have not had good methods to measure oxygen in the brain and how it is distributed and whether some areas of the brain have low oxygen in connection with disease.

However, researchers have developed a revolutionary method to closely monitor oxygen in the brain.

The method shows that inactivity leads to hypoxic (oxygen-poor) pockets in the brain, which can probably contribute to the development of neurodegenerative diseases such as Alzheimer's.

“With this method, we can study whether drugs or exercise can oxygenate the hypoxic areas of the brain and counteract disease. Finally being able to study oxygen in the brain is incredibly exciting,” explains a researcher involved in developing the method, Maiken Nedergaard, Professor, Center for Translational Neuromedicine, University of Copenhagen, Denmark and Center for Translational Neuromedicine, University of Rochester, NY, USA.

The research has been published in Science.

Previous methods inadequate

Researchers have long dreamed of being able to study oxygen in the brain.

Current methods can give researchers some insight into what they are seeking. However, these methods have flaws.

For example, researchers can study oxygen distribution by applying an electrode directly to the brain. However, this destroys the brain tissue where the electrode is attached and only enables oxygen to be studied in a very small region of the brain.

Another method involves very expensive microscopes and a toxic phosphorescent substance that can only be injected into the brain. This also damages the brain tissue, and none of the methods provide insight into what is happening throughout the brain.

“This has meant that we have very little knowledge about the basal oxygen level in the brain and how the concentration of oxygen in the brain changes over time or in different regions in the brain,” says Maiken Nedergaard.

Enzymes from fireflies light up in the brain

The method the researchers developed approaches the problem differently and uses modified enzymes from fireflies.

These enzymes emit photons (that is, they glow) when they come into contact with oxygen and a special substrate.

When the researchers injected mice with the enzyme and substrate, the regions of the mouse brains that are rich in oxygen begin to light up, and the hypoxic regions remain dark.

To study the distribution of oxygen in the brain, the researchers placed the mice in a completely dark chamber.

The researchers glued a metal plate to the heads of the mice to hold the skulls under a camera that photographs the light as it flows out through the skull.

The mice were placed on an air-supported polystyrene ball that moved under them, just as if they were running or walking. The researchers thus studied differences in oxygenation in the brain during physical activity and inactivity.

“This is a really good method for visualising oxygen in the brain. Our method is 10,000 times more sensitive than fluorescent proteins. We found that the oxygen level in the brain is not constant all the time,” explains Maiken Nedergaard.

Exercise oxygenates the brain

With the method, the researchers have already obtained great insight into what happens to oxygen in the brain under given conditions.

For example, they saw how activity stimulates good oxygen saturation of the entire brain, whereas inactivity leads to hypoxic pockets in the brain.

Lacking oxygen is particularly bad for the brain’s neurons, and the researchers also have a theoretical explanation for what happens in the brain when the hypoxic pockets occur in connection with physical inactivity.

Maiken Nedergaard explains that the biology behind blood vessels is not quite as positive as we might think. For example, white blood cells are very large and can have difficulty passing through the thinnest capillaries, such as those in the brain.

Low blood pressure associated with a lack of physical activity can result in the white blood cells blocking the blood vessels in the brain, leading to a lack of oxygen.

Conversely, exercise can increase blood pressure and remove the blocking white blood cells, so that oxygen can once again reach the brain.

The researchers found that the hypoxic pockets in the brain disappeared when they forced the mice to move their feet on the ball.

“We show for the first time that a phenomenon with the white blood cells called capillary stalling is associated with a lack of oxygen in the brain. Previous research has pointed out that capillary stalling is associated with getting old and getting Alzheimer’s. It’s probably pretty bad when this happens,” says Maiken Nedergaard.

Mental gymnastics may oxygenate the brain

According to Maiken Nedergaard, the method opens up a new era in studies of the brain because researchers can now study what happens to oxygen in the brain in connection with the development of Alzheimer’s or traumatic brain injury.

“We can measure oxygen concentrations throughout the brain, and we can look for signs of brain damage or neurodegeneration very early in the development of disease. We can also see whether interventions can reduce harmful oxygen deficiency in the brain and what exercise and medication can do,” explains Maiken Nedergaard.

She elaborates that one thing that will also be very interesting to investigate is how brain exercise affects the oxygenation of the brain.

“They usually say that professors never develop dementia. It will be interesting to see if keeping the brain active by solving complex tasks has the same effect as physical exercise in terms of preventing the presence of oxygen-poor pockets in the brain and accompanying disease,” says Maiken Nedergaard.

However, she also emphasises that the method can only be used on mice, since the human skull is too thick for the photons from the firefly enzymes to penetrate.

Oxygen imaging of hypoxic pockets in the mouse cerebral cortex” has been published in Science. The research was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the United States National Institutes of Health, the United States National Institute of Neurological Disorders and Stroke, the Simons Foundation, Independent Research Fund Denmark, the Lundbeck Foundation, JPND Neurodegenerative Disease Research, US Army Research Office grants, a Marie Skłodowska-Curie Fellowship, an ONO Rising Star Fellowship and the Novo Nordisk Foundation.

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