Understanding how the brain reacts when a neuron dies could be a key to unlocking the secrets behind aging and recovery from various neurological disorders.
Recently, Yale School of Medicine researchers set out to study the complex interactions between dying neurons and the glial cells in the central nervous system that are responsible for clearing dead cells and debris from the brain.
The researchers likened ridding the brain of dead cells to garbage collection. “If you were to stop collecting garbage in New York City, you wouldn’t be able to get in. There would be debris everywhere,” says Eyiyemisi Damisah, MD, assistant professor of neurosurgery at Yale School of Medicine. The brain, just like New York City, requires efficient garbage disposal. If dying or infected cells are not properly removed, the debris may damage the nervous system.
One of the major challenges facing such research is the lack of tools available to understand this process in the brain of living humans. Many cells die during growth and development in a brain each day, but actually observing what is known as “corpse removal” in a living organism has been limited.
That’s because the timing and location of cell death is unpredictable. It can also happen very quickly, which makes it hard to capture visually or to understand with precision.
To address these challenges, co-lead authors Drs. Damisah and Robert Hill, Ph.D., assistant professor of biological sciences at Dartmouth College, developed innovative photochemical and viral methods to induce death in single brain cells in live mice while working together as fellows in Jaime Grutzendler, MD’s lab.
In a paper published in Science Advances on June 26th, 2020, they called this technique “2Phatal.” Using fluorescent markers, they were able to watch the glia cells communicate and remove dead cells with live in vivo time lapse optical imaging. “This is the first time the process has ever been seen in a live mammalian brain,” explains Dr. Jaime Grutzendler, the Dr. Harry M. Zimmerman and Dr. Nicholas and Viola Spinelli Professor of Neurology and Neuroscience at Yale School of Medicine.
The 2Phatal technique is quite clever. “Rather than hitting the brain with a hammer and causing thousands of deaths, inducing a single cell to die allows us to study what is happening right after the cells start to die and watch the many other cells involved [in removing it],” says Dr. Grutzendler. “This was not possible before. We are able to show with great clarity what exactly is going on and understand the process.”
The authors revealed that microglia, astrocytes, and NG2 cells (three types of glial cells in the central nervous system) work in a highly coordinated manner to remove dead cells and debris. Each cell type has a different function, with precise boundaries dividing the labor of what “eats” what, says Dr. Damisah. However, if one cell loses its ability to sense the dying cell and engulf it, other cells take over—possibly at a slower pace—but the job still gets done.
The researchers also noticed that glial cells took at least twice as long to remove the neuronal corpse in the aged brain, but this delay was not due to the ability of aged glia to sense that the cell was dying.
This observation about aging could have important implications for neurodegeneration and the functional decline of the brain, Dr. Grutzendler notes. “Presumably, if cells are dying and there is inefficient removal of them, the debris could be causing further damage and inflammation,” he says.
The work opens up a number of other studies that may have impact on understanding brain development, injury, and neurodegeneration. “Cell death is very common in diseases of the brain,” says Dr. Damisah. “And understanding the process might yield insights on how to address cell death in an injured brain from head trauma to stroke and other conditions.
Dr. Grutzendler agrees. “Following injury to the brain, you need to understand what the cells are doing and what molecules are involved in order to develop new strategies to treat the condition. And if we can remove dying cells efficiently, can we prevent age-related neurodegeneration?”
The results of their work is featured in “Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo,” published in Science Advances on June 26th 2020.