How Bird Retinas Function Without Oxygen May Inform Future Stroke Therapies

Neural tissue normally dies quickly without oxygen. Yet bird retinas—among the most energy-demanding tissues in the animal kingdom—function permanently without it. An international research team has now discovered how birds have solved this biological paradox. The scientists’ study showed that the inner parts of the bird retina operate under chronic oxygen deprivation, relying instead on anaerobic energy production. Their findings also overturn a long-standing assumption about a mysterious structure in the bird eye—the pecten oculi—that has puzzled scientists since the 17^th century.

The collective findings may be relevant in future treatment of stroke patients, the authors suggest. “In conditions like stroke, human tissues suffer because oxygen delivery is reduced and metabolic waste accumulates,” said Jens Randel Nyengaard, MD, PhD, professor in the department of clinical medicine at Aarhus University. “In the bird retina, we see a system that copes with oxygen deprivation in a completely different way.”

Nyengaard is senior author of the team’s published paper in Nature, titled “Oxygen-free metabolism in the bird inner retina supported by the pecten.”

The extraordinarily high metabolism of neural tissues in warm-blooded animals requires a continuous and ample supply of oxygen and nutrients to support aerobic metabolism, the authors wrote. Most animals supply neural tissue with oxygen through dense networks of tiny blood vessels. “Neural tissues are exceptionally sensitive to oxygen deprivation and rely on a dense network of blood vessels to support their extraordinarily high metabolic demands for oxygen, nutrients and clearance of waste products.”

The retina, a highly specialized extension of the brain, is no exception, and in fact consumes more energy than any other tissue in the body. In many animals extra blood vessels in the retina are needed, even though this interferes with light transmission to photoreceptors, as blood vessels scatter light in its path to the photoreceptor. Birds, however, present something of a paradox. Their retinas are avascular, meaning there is a lack blood vessels within the retinal tissue itself. This feature is thought to improve visual acuity, but how the retina survives without a blood supply has remained unknown.

“Our starting point was simple,” says biologist and first author Christian Damsgaard, PhD, associate professor at Aarhus University in Denmark. “According to everything we know about physiology, this tissue should not be able to function.” While the starting point may have been simple, the journey to the end point was anything but simple. It has taken Damsgaard and a growing team of researchers, mostly from Aarhus University, eight years to produce the results.

For centuries, the prevailing explanation has been that a structure called the pecten oculi—a comb-like, highly vascularized organ protruding into the vitreous body of the bird eye—supplies oxygen to the retina. The structure has been known since the 1600s, but its precise function has remained speculative. One reason, the researchers note, is that no one had directly measured oxygen levels in the bird retina under normal physiological conditions. “The established hypothesis is that these structures supplement the retina with the additional oxygen needed to maintain retinal oxygenation,” the researchers noted. “However, this hypothesis has never been confirmed by intraocular oxygen flux measurements.” Nyengaard continued, “Doing so is technically extremely challenging. You need to keep the animal under stable, normal physiological conditions while performing very delicate measurements.”

In 2020, the team was able to do exactly that, thanks to a collaboration with veterinary anesthesia expert and assistant professor Catherine Williams, PhD, also from Aarhus University. The results were unexpected, showing that the pecten does not deliver oxygen to the retina at all. Measurements showed that the inner layers of the retina exist in a state of permanent oxygen deprivation, with roughly half of the retinal tissue receiving no oxygen. “… our data show that oxygen diffusion limits the retinal oxygen supply and that the inner retina of zebra finches is fully anoxic under normal physiological conditions,” they wrote. “… we provide data against the prevailing hypothesis. Our data indicate that the pecten does not function as the primary oxygen supplier to the avian retina, resulting in inner retinal anoxia.”

If the retina receives no oxygen, then how does it produce enough energy to function? To answer that question, the researchers embarked on a multi-year investigation combining physiology, molecular biology, imaging, and computational analysis. Using spatial transcriptomics, the team mapped the expression of thousands of genes across thin sections of the retina, allowing them to see where specific metabolic pathways were active within the tissue. Spatial transcriptomics is a technology that maps gene expression directly within intact tissues, revealing both what genes are active and where they are active. “We were not looking at one or two genes, but at 5,000 to 10,000 genes at once, each mapped to a precise location,” said Damsgaard. “That gave us a kind of molecular GPS.”

The data revealed a striking pattern, indicating that genes involved in anaerobic glycolysis—the breakdown of sugar without oxygen—were highly active in the oxygen-deprived inner layers of the retina. This finding, however, raised yet another problem. Anaerobic glycolysis produces roughly fifteen times less energy than oxygen-based metabolism per sugar molecule.

“This mismatch raised yet another question: How can one of the most energy-hungry tissues in the body survive on such an inefficient process?” Nyengaard noted.

The answer emerged through further imaging studies. Using radiolabeled sugar and autoradiography, the researchers showed that the bird retina takes up glucose at much higher rates than the rest of the brain. By revisiting their spatial transcriptomics data, the researchers identified high expression of glucose and lactate transporters in the pecten.

The structure, they found, serves as a metabolic gateway, delivering large amounts of sugar into the retina and removing lactate, a waste product of anaerobic metabolism, back into the bloodstream. The collective data, they stated, “… indicate that the pecten provides metabolic support for anaerobic metabolism to the anoxic inner retina and serves as a reverse exchanger of glucose, lactic acid and CO2 between the retina and the blood.” Nyengaard added, “The pecten is not an oxygen supplier. It is a transport system for fuel in and waste out.”

The discovery fundamentally changes the understanding of a structure that has been misinterpreted for centuries. “Our direct assessment of the function of the pecten enables us to confidently reject the hypothesis that the pecten provides sufficient retinal oxygen supply to maintain retinal oxygenation,” the authors concluded. “We are essentially collapsing one house of cards and replacing it with another,” Nyegaard further stated. “House of cards, because scientific findings are not set in stone. New results can add new knowledge. That is how science progresses.”

The researchers note that avoiding oxygen and blood vessels in the retina likely confers an optical advantage, improving visual sharpness. Evolutionary evidence suggests that this trait arose in the dinosaur lineage leading to modern birds. And while the study represents purely fundamental research, the authors point out that the findings may have broader implications.

“Nature has solved a physiological problem in birds that makes humans sick,” Nyeegard noted. “We hope that understanding this evolutionary solution can inspire new ways of thinking about why tissues fail under oxygen deprivation in disease, and how such diseases can be treated.”