Bioluminescence Unveils Brain’s Oxygen Pathways

Summary: A new study introduces a new bioluminescence imaging technique to observe the movement of oxygen in the brains of mice. This method, inspired by firefly proteins, reveals widespread patterns of oxygen distribution in real time, providing insight into conditions such as hypoxia caused by strokes or heart attacks.

It further explores how sedentary lifestyles could increase the risk of Alzheimer’s disease by detecting “hypoxic pockets” or areas of temporary oxygen deprivation. This research paves the way for a better understanding of diseases associated with brain hypoxia and the testing of therapeutic interventions.


  1. A new bioluminescence imaging technique now allows scientists to observe the movement of oxygen in the brain, providing detailed views in real time.
  2. The method shows that certain areas of the brain can experience temporary oxygen deprivation, called “hypoxic pockets”, which are more common in sedentary states and could be linked to an increased risk of Alzheimer’s disease.
  3. This research, which links work from the University of Rochester and the University of Copenhagen, can revolutionize our understanding of diseases associated with brain hypoxia and pave the way for new therapeutic interventions.

Source: University of Copenhagen

The human brain consumes large amounts of energy, which is almost exclusively generated by some form of metabolism requiring oxygen. Therefore, efficient and timely allocation and delivery of oxygen is essential for proper brain function. However, the precise mechanisms of this process have remained largely hidden from scientists.

A new bioluminescence imaging technique, described today in the journal Sciencecreated highly detailed and visually striking images of the movement of oxygen in the brains of mice.

The method, which can be easily replicated by other laboratories, will allow researchers to more precisely study forms of hypoxia, such as the denial of oxygen to parts of the brain that occurs during a stroke or a heart attack. This already helps to understand why a sedentary lifestyle increases the risk of diseases such as Alzheimer’s disease.

“This research demonstrates that we can monitor changes in oxygen concentration continuously and across a broad area of ​​the brain,” says Maiken Nedergaard, co-director of the Center for Translational Neuromedicine, based at both the University of Rochester and the University of Copenhagen.

“This gives us a more detailed picture of what is happening in the brain in real time, allowing us to identify previously undetected areas of temporary hypoxia, which reflect changes in blood flow that can trigger neurological deficits », explains Maiken Nedergaard.

Fireflies and serendipitous science

The new method uses luminescent proteins, chemical cousins ​​of bioluminescent proteins found in fireflies. These proteins, used in cancer research, use a virus to instruct cells to produce a luminescent protein in the form of an enzyme. When the enzyme meets its substrate called furimazine, the chemical reaction generates light.

Like many important scientific discoveries, using this process to image oxygen in the brain was discovered by chance. Felix Beinlich, an assistant professor at the Center for Translational Neuroscience at the University of Copenhagen, initially planned to use luminescent proteins to measure calcium activity in the brain. It became clear that there was an error in the protein production, leading to a research delay of several months.

While Felix Beinlich waited for a new batch from the manufacturer, he decided to continue experiments to test and optimize the monitoring systems. The virus was used to deliver enzyme production instructions to astrocytes, ubiquitous support cells in the brain that maintain the health and signaling functions of neurons, and the substrate was injected directly into the brain.

The recordings revealed activity, identified by fluctuating intensity of bioluminescence, which the researchers suspected and would later confirm reflected the presence and concentration of oxygen. “In this case, the chemical reaction depended on oxygen. So when there is the enzyme, the substrate and the oxygen, the system starts to glow,” explains Felix Beinlich.

While existing oxygen monitoring techniques provide information on a small area of ​​the brain, the researchers observed, in real time, the entire cortex of the mice. The intensity of the bioluminescence corresponded to the concentration of oxygen, which the researchers demonstrated by changing the amount of oxygen in the air the animals breathed.

Changes in light intensity also corresponded to sensory processing. For example, when mice’s whiskers were stimulated by a puff of air, researchers could see the corresponding sensory region of the brain light up.

“Hypoxic pockets” could indicate Alzheimer’s risk

The brain cannot survive for long without oxygen, a concept demonstrated by the neurological damage that quickly follows a stroke or heart attack. But what happens when small parts of the brain are deprived of oxygen for brief periods?

This question wasn’t even asked by researchers until Nedergaard’s lab team began looking closely at the new recordings. By monitoring the mice, the researchers observed that specific tiny areas of the brain darkened intermittently, sometimes for several seconds, meaning the oxygen supply was cut off.

Oxygen travels throughout the brain via a vast network of arteries and smaller capillaries – or microvessels – that permeate brain tissue.

Through a series of experiments, the researchers were able to determine that oxygen was being denied due to capillary blockage, which occurs when white blood cells temporarily block microvessels and prevent the passage of oxygen carrying red blood cells.

These areas, which the researchers called “hypoxic pockets,” were more prevalent in the brains of mice when they were resting than when the animals were active. Capillary blockage is thought to increase with age and has been observed in models of Alzheimer’s disease.

“The door is open to studying a range of diseases associated with brain hypoxia, including Alzheimer’s disease, vascular dementia and long COVID, as well as how a sedentary lifestyle, aging, hypertension and other factors contribute to these diseases,” says Maiken Nedergaard. and adds:

“It also provides a tool to test different medications and types of exercise that improve vascular health and slow the progression to dementia.”

Other authors include Antonios Asiminas of the University of Copenhagen, Hajime Hirase of the University of Rochester, Verena Untiet, Zuzanna Bojarowska, Virginia Plá and Björn Sigurdsson of the University of Copenhagen, as well as Vincenzo Timmel, Lukas Gehrig and Michael H. Graber from the University of Applied Sciences and Arts of North-West Switzerland.

Funding: The study was supported by funding from the National Institute of Neurological Disorders and Stroke, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Novo Nordisk Foundation, the Lundbeck Foundation, the Fund Independent Research Institute of Denmark and the US Army Research Office.

About this neuroscience research news

Author: Liva Polack
Source: University of Copenhagen
Contact: Liva Polack – University of Copenhagen
Picture: Image is credited to Neuroscience News

Original research: Closed access.
“Oxygen imaging of hypoxic pockets in the mouse cerebral cortex” by Maiken Nedergaard et al. Science


Oxygen imaging of hypoxic pockets of the mouse cerebral cortex

Consciousness is lost within seconds after cerebral blood flow stops. The brain cannot store oxygen and disruption of oxidative phosphorylation is fatal within minutes. However, only rudimentary knowledge exists regarding cortical partial oxygen tension (P.o2) dynamic under physiological conditions.

Here we present Green Enhanced Nano-Lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for P.o2 imagery.

In awake mice, we discover the existence of spontaneous and spatially defined “hypoxic pockets” and demonstrate their link to the abrogation of local capillary flow. Exercise reduced hypoxic pocket burden by 52% compared to rest.

The study provides insight into cortical oxygen dynamics in awake animals and simultaneously establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.

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