STANFORD, Calif. – The central nervous system, made up of the brain and spinal cord, never forgets a slight. Somehow, nerve cells lose the ability to regenerate: witness actor Christopher Reeve’s paralysis after his horse threw him at a jump. To find a cure for such injuries, scientists must understand why nerve cells lose the ability to grow back. They know that these cells – called neurons – stop regenerating because a signal tells them to slow down during development. The problem is, scientists haven’t known much about that signal.
Now, a team of Stanford University Medical Center researchers have identified the mechanism and some key cells involved in controlling regeneration. It turns out that the signal to slow down doesn’t come from the neurons themselves, but from an outside source. The signal’s effects appear to be permanent. The findings, published in the June 7 issue of Science, outline what may be a new avenue to explore in the search for brain-damage and paralysis treatments, the researchers say.
Messages move through the average neuron like tributaries flowing into a river. The tributaries are called dendrites, and they flow into the axon, the river itself, which in turn can share messages with dendrites further downstream.
When Reeve fell from his horse, neurons that weren’t killed outright may have had their axons chopped in half, disconnecting them from the network. “This is the core problem in neural degenerative diseases, especially things like spinal cord injury. Axons that get cut don’t grow past the site of the injury back to normal connections in the brain,” said Jeffrey Goldberg, lead author of the paper and senior graduate student in the lab of Ben A. Barres, MD, PhD, associate professor of neurobiology and developmental biology. “When a person is paralyzed, that’s permanent,” he said.
Left to their own devices, neurons in the central nervous system grow back so slowly that they often die before regaining contact with other nerves. Most scientists blame this inability to regenerate on a group of nursemaid cells called glia, stationed around neurons. But Golderg’s work suggests that while glia cells slow axon growth, they’re not the only problem. Goldberg said that while neurons are developing, they get an outside signal they never forget. The message is: stop growing your axon so rapidly and start working on your dendrites.
To show that glial cells weren’t solely responsible for the axon’s slow regeneration, Goldberg removed the glia from axons in the optic nerves of embryonic and 8-day-old rats. (The optic nerve, which connects the brain to the eyeball, is an extension of the brain and is as injury-intolerant as the rest of the central nervous system.) Even without the glia, the embryonic neurons still regenerated 10 times faster than the neurons that developed in the 8-day-old rats.
From these results, Goldberg speculated that neurons had an internal clock that determined when they were destined to stop regenerating. To test his theory, Goldberg kept groups of isolated embryonic neurons alive in his laboratory until they were the same age as neurons in the 8-day-old rats. These lab-grown neurons were still able to regenerate axons quickly, while those taken from the recently born rats showed much slower axon growth.
These results told Goldberg that age was not the key to an axon’s inability to regenerate. Rather, a signal that the neuron encountered in the developing rat must confer the “stop regenerating” message. Now, he had to find the culprit. “I asked if it was hormonal changes that happen at birth and found that it wasn’t. So then I asked what kinds of cell types interact with the neurons,” Goldberg said. At first he assumed the slow-down signal came from the site to which the axon grows. Upon researching that idea, he discovered instead that the signal was coming from the retina’s interaction with the dendrites.
Looking closer, he found that the neurons only needed to be in direct contact with one type of retinal cells, called amacrine cells, to permanently lose the ability to grow axons quickly. Amacrine cells help collect and process information from the eye’s photoreceptors – rods and cones. Interestingly, when an amacrine cell sent its stop order, the neurons more than doubled their number of dendrites. By figuring out that amacrine cells permanently change neuron behavior, Goldberg found the mechanism that controls regeneration. And that discovery may give the scientific community a way to treat central nervous system injuries.
“Christopher Reeve’s injury in 1995 really energized a lot of fundraising and interest in the field. It’s an exciting field because there’s a lot of energy going into understanding why the central nervous system fails to regenerate,” said Goldberg. “There’s a lot of hope right now that in coming years and decades we’ll be able to offer new treatments to patients.”
Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.