How the brain decides where to insulate its own wiring

In the complex circuitry of the brain, a fatty substance known as myelin plays a vital role in insulating neural wiring. It coats billions of axons in the brain and makes up about one-fifth of the organ in humans.

But just how this essential substance is laid down — and how it is customized in diverse types of specialized brain cells — has remained mysterious. By revealing some of the molecular signals that govern this process, a new study by Harvard biologists takes a step toward illuminating brain development and providing clues that may lead to therapies for devastating neurological disorders.

“Knowing how myelination is established is important not only for understanding normal brain development, but also for shedding light on neurodevelopmental and neurodegenerative diseases associated with myelin defects,” said lead author Nuria Dominguez-Iturza, a postdoctoral researcher in the Department of Stem Cell and Regenerative Biology. “By understanding how myelination normally occurs, we can better understand what goes wrong in these diseases.”

In the new paper, published in the journal Developmental Cell, Dominguez-Iturza and her co-authors sought to understand how neurons interact with myelin-producing cells called oligodendrocytes.

Neurons have long axons that transmit signals to other cells; the longest ones in the human body extend about one meter from the brain to the lower spinal cord. Like electrical wires, they are insulated to facilitate the transmission of signals, in this case by fatty myelin.

In 2014, the lab of Paola Arlotta, Golub Family Professor of Stem Cell and Regenerative Biology, published a landmark paper showing that myelination is not a generic, one-size-fits-all process and instead follows varied patterns in different neurons. For example, some axons are thickly insulated while others have long stretches of unmyelinated tracts. The study found that myelin distribution was specified by a dialog between neurons and myelin-producing cells and represented a key feature of neural identity.

What drives the process of “differential myelination” — in which different regions of the brain and nervous system are coated by variable amounts of myelin – has remained unknown. This study sought to answer that question.

In an investigation that spanned more than four years, researchers examined myelination and myelin-producing cells in mice from early postnatal development to adulthood using methods such as single-cell RNA sequencing and in utero electroporation (a technique that uses injections and electrical pulses to deliver selected genes to targeted cells in the developing mouse brain).

They created an “interactome”: an atlas of the interactions of chemical signals between neurons and oligodendrocytes to see how they played out in different layers of the cortex over time. They also performed experiments on live mice.

The researchers examined whether different types of oligodendrocytes drove differential myelination in the cortex, but they found no evidence of that. Instead, the same types of oligodendrocytes performed differently based on their maturation stage and location in the cortex. But investigators found the neurons themselves did influence this process through signals to the oligodendrocytes.

They showed that different types of pyramidal neurons could control both oligodendrocyte maturation and the distribution of myelin across layers of the cortex. They identified two different molecules that promoted myelination; when these signals were blocked, myelination decreased.

Arlotta — who believes that many more signals remain to be discovered — described myelination as “a very nuanced process that serves the function of different classes of neurons in different ways.” For example, some neurons might perform fast signaling and require thickly insulated axons while others may require uncovered axons open to connections with other cells. The new study shows that the neurons themselves have a say in how they are myelinated.

“The brain uses different mechanisms to achieve nuances,” Arlotta said. “Perhaps every neuron has myelin on its axons, but not every neuron is myelinated by oligodendrocytes the same way.”

The process of myelination continues well into adulthood. Indeed, the process plays a central role in learning and memory and helps the brain remain plastic and adaptable.

This study examined only differences in myelin distribution between the six layers of the neocortex. In subsequent studies, Dominguez-Iturza will examine differences between individual cells to illuminate how myelin is distributed on different portions of the same axon.

By understanding these mechanisms, scientists can gain insights about brain development and treating myelin-related diseases such as multiple sclerosis.

“It’s an example of basic science and curiosity-driven science that aims to understand how things work,” Arlotta said. “This is a very important process, and it’s already pointing us toward the identification of molecules and mechanisms that could be exploited in the context of disease. It has value for thinking about therapies and giving us tools to fix demyelinating diseases. I think that's an example of the power of basic science.”

This research was supported by the National Institute of Health, under grants R01NS128117 and R01NS103758.