Precise Locations of Oligodendrocytes, Myelin Density Mapped Across Mouse Lifespan

Researchers headed by a team at Johns Hopkins School of Medicine have used 3D imaging, special microscopes, and artificial intelligence (AI) to construct maps that show the precise location of more than 10 million oligodendrocytes and assess myelin density in mouse brains.

The new maps help to paint a whole-brain picture of how myelin content varies between brain circuits, and also provide insight into how the loss of oligodendrocytes impacts human diseases such as multiple sclerosis (MS), Alzheimer’s disease, and other disorders that affect learning, memory, sensory ability, and movement. Although mouse and human brains are not the same, they share many characteristics and most biological processes.

“Our study identifies not only the location of oligodendrocytes in the brain, but also integrates information about gene expression and the structural features of neurons,” said Dwight Bergles, PhD, the Diana Sylvestre and Charles Homcy professor in the department of neuroscience at Johns Hopkins University School of Medicine. “It’s like mapping the location of all the trees in a forest, but also adding information about soil quality, weather and geology to understand the forest ecosystem.”

Bergles is senior and corresponding author of the team’s published paper in Cell, titled “Brain-wide mapping of oligodendrocyte organization, oligodendrogenesis, and myelin injury.” In their paper they concluded, “These studies of oligodendrocyte density,  oligodendrogenesis, and myelin distribution provide new insight into the dynamic patterning of oligodendrocytes in the mammalian brain and the means to determine how this process is influenced by life experience, aging, and disease.”

In the brain, myelin is produced exclusively by oligodendrocytes, the authors explained. Myelin acts as the protective sleeve around nerve cell axons, which speeds transmission of electrical signals and supports brain health. “Many axons in the mammalian CNS are ensheathed by myelin, a multilamellar membrane that acts as insulation to accelerate the propagation of action potentials and reduce energy expenditure,” they wrote.

Oligodendrocytes are found in nearly every area of the brain, even though myelin is more prevalent in white matter, which serves as the main highway for neural circuits connecting different regions of the brain. The distribution of oligodendrocytes and myelin also varies significantly between different cortical and subcortical areas of the brain, the researchers continued. “Although the density of myelin varies between neuron types, brain regions, ages, and life experiences, there has been no comprehensive analysis of oligodendrocyte distribution across the lifespan to quantify these differences … Mapping these patterns across the brain would help reveal how myelin is used to endow brain circuits with distinct functional characteristics and determine how loss of oligodendrocytes, due to injury, aging, or disease, impacts sensory, motor, and cognitive processes.”

For their new mapping project Bergles’ team, including first author Yu Kang T. Xu, a PhD student and Kavli Neuroscience Discovery Institute fellow, collaborated with biomedical engineers and computer scientists. They developed a novel pipeline involving tissue clearing, which removes fatty deposits that make it hard to see deep in the brain, along with a fast type of imaging called light-sheet microscopy, to rapidly scan through all brain structures.

To catalog over 10 million cells per mouse brain in various conditions and timespans, the scientists needed help from machine learning, a technology that teaches computers how to accurately perform tasks—in this case, to automatically search through images and identify each oligodendrocyte, then reconstruct brainwide maps, one image at a time.

Each map charted positions of oligodendrocytes at certain times over the mouse lifespan, from age two months to two years. The results indicated that, with age, animals steadily acquired more oligodendrocytes, but the rate of new oligodendrocyte and myelin formation varied dramatically between different brain regions. Areas that had slow addition at first continued to add oligodendrocytes slowly later in life—they didn’t suddenly catch up or show dramatic variability—suggesting that this patterning reflects a fairly rigid developmental program.

They found that brain regions that received direct sensory input had three times more oligodendrocytes than other areas such as the primary motor cortex. This difference may reflect the brain’s need to have myelin-wrapped neurons with faster transmission located in areas that need to process sensory information—touch, sound and sight, for example—very quickly. Oligodendrocyte and myelin formation were very prolonged in areas of the mammalian brain, such as the hippocampus, which are key to the formation and storage of learning and memory.

“This analysis revealed the remarkable heterogeneity in oligodendrocyte distribution between brain regions—spanning over four orders of magnitude—and the enhanced rate of oligodendrogenesis in select cortical areas, highlighting sustained plasticity in circuits that support executive function, memory, and emotional processing,” the investigators wrote. “These atlases revealed the diversity of oligodendrocyte patterning, which was consistent between brain hemispheres, individuals, and sexes but displayed both age- and region-specific differences. Integration of these atlases with transcriptomic and ultrastructural datasets highlighted underlying mechanisms that may control this patterning.”

In mice exposed to chemicals that destroy oligodendrocytes and myelin, the scientists identified regions of higher vulnerability and greater resilience, which may yield clues to preserving myelin in diseases such as multiple sclerosis. “In response to cuprizone-induced demyelination, oligodendrocytes exhibited regional differences in their susceptibility to injury and regeneration,” they stated. “Recovery from demyelination was also variable, with deeper layers of motor and somatosensory cortex recovering exceptionally fast, despite also experiencing the most severe loss during injury.”

Finally, in a mouse model of Alzheimer’s disease, the team found that myelin was not only damaged in areas near amyloid-beta plaques called dense core plaques (a tangle of misfolded proteins that are a hallmark of Alzheimer’s disease), but also in white matter regions with only diffuse plaques. This increased vulnerability may explain why oligodendrocyte dysfunction is prevalent in this disease, Bergles suggests.

“In models of demyelination and disease, we identified regions of enhanced oligodendrocyte resilience and vulnerability and white matter injury near β-amyloid plaques, demonstrating the utility of this pipeline for defining brain-wide oligodendrocyte dynamics in both health and disease,” the scientists stated.

The new atlases provide higher resolution and better coverage of gray matter than previously published maps, they say. Myelin in these areas is harder to see using techniques such as MRI. Gray matter houses most of the neurons in the brain and controls movement and other functions.

“Because myelin can speed communication between neurons, these maps of regional differences in myelin patterning may help us understand how different parts of the brain accomplish different tasks,” Bergles commented. “It will be interesting to use this approach to see how different life experiences, such as stress, social interaction, and learning affect these patterns.”

These newly published oligodendrocyte maps can be explored free of charge by other scientists, says Bergles, with hopes such use will hasten new discoveries.