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Researchers Investigate Genes Involved in Brain Repair after Stroke

For release: Friday, January 28, 2011

Labeling of axons in the mouse brain reveals a much larger field of axons after a stroke.  Courtesy of Dr. Carmichael, UCLA

A stroke can kill millions of brain cells within minutes, leaving an area of nonviable brain tissue surrounded by a halo of surviving cells.  A fraction of these surviving neurons grows vigorously, sprouting new branches (or axons), making new connections and contributing to recovery.  Identifying what drives this sprouting may lead to therapies that improve recovery.

Toward that end, researchers funded by the National Institute of Neurological Disorders and Stroke (NINDS) compared the gene activity patterns of sprouting and non-sprouting neurons in rats after a stroke.  They also examined how these gene activity patterns changed with age.

"We found that there are unique genetic programs associated with the growth of new axonal connections after a stroke, and that these programs change dramatically with age," said senior author S. Thomas Carmichael, M.D., Ph.D., an associate professor of neurology at the David Geffen School of Medicine, University of California, Los Angeles.

The study was published in Nature Neuroscience.*

Until now, researchers were unable to sort through the jumble of axons in the brain and separate the neurons that sprout after a stroke from their non-sprouting neighbors.  Dr. Carmichael and his team developed a way to find newly sprouted axons by using colorful tracers that are absorbed at the axon tip.  They injected one tracer into the brain at the time of stroke, followed by a distinct tracer at the same site one to three weeks later.  Axons that took up both tracers must have been present at the time of stroke and persisted afterward.  But axons that took up only the second tracer must have sprouted after the stroke.

Next, the researchers used a laser to extract the sprouting and non-sprouting neurons, and measured the activity of thousands of genes inside the cells.  They also compared the sprouting response in rats at a few months old to rats at age two, considered elderly in rat years. 

The largest changes in gene activity occurred in young animals within one week after stroke.  However, at all ages and time points studied, the sprouting neurons activated or deactivated hundreds of genes, many of which have been previously implicated in brain development.

In follow-up experiments, the researchers analyzed the role of several genes whose activity increased with sprouting in the older rats.  Those genes are of interest because most strokes occur in older people, with the risk doubling each decade between 55 and 85.

"We chose to focus on genes that have very different functions and seem to work at different control points in the sprouting process," Dr. Carmichael said.  Three of those genes were ATRX, IGF1 and Lingo1:

  • ATRX.  This gene is known to support neuronal survival and help neurons reach their proper locations in the developing brain.  The researchers found that in the aged brain ATRX supports axon sprouting.  Blocking ATRX function after a stroke blocked the sprouting response.
  • IGF1.  This growth factor supports axon sprouting during brain development.  But the researchers found that blocking IGF1 function one week after stroke not only kept neurons from sprouting, it killed them.  Until now experts thought that neuronal death ended within a few days of stroke, but this shows that neurons continue to struggle for survival for at least a week, Dr. Carmichael said.
  • Lingo1.  The Lingo1 protein inhibits neuronal growth, and in animal studies blocking Lingo1 can improve recovery from spinal cord injuries.  Paradoxically, Lingo1 is one of the genes that become more active in sprouting neurons after a stroke.  An antibody that blocks Lingo1 increased sprouting.

These three genes are promising targets for drug therapy, but there are challenges ahead, according to Dr. Carmichael.  First, it is unclear how such drugs would be delivered.  Repeated injections into the brain would be difficult and potentially harmful for stroke patients, who are often medically unstable, he said.  However, the study shows that a biopolymer implant can steadily release molecules (such as the Lingo1 antibody) into the rat brain over several weeks.

Another step is to test whether changing the activity of genes like Lingo1 can restore movement, sensation and other functions after a stroke.  These experiments are underway in animal models, Dr. Carmichael said.

"We hope that if we block growth inhibitors or turn on growth promoters, the new connections that are formed will be beneficial.  But that might not always be the case.  The adult brain probably has systems in place to control the formation of unneeded or excessive connections," he said.

- By Daniel Stimson, Ph.D.

*Li S et al.  "An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke."  Nature Neuroscience, December 2010, Vol. 13, pp. 1496–1504.

Labeling of axons in the mouse brain reveals a much larger field of axons after a stroke. Courtesy of Dr. Carmichael, UCLA.
This image illustrates the degree of axonal sprouting that can take place after a stroke. Dr. Carmichael and his team created maps of the axons in the sensorimotor cortex of mice. Maps from several mice – some normal and some after a stroke – have been superimposed. The light blue dots are axons in normal mice and the red dots are axons three weeks after a stroke. Image courtesy of Dr. Carmichael.

Last Modified January 28, 2011