Science + Technology

UCLA Study Identifies Cellular Cues for Stroke Recovery

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When a stroke strikes, thesupply of blood to the part of the brain affected is interrupted, starving itof oxygen. Brain cells can be seriously damaged or die, impairing local brainfunction.

But the brain is a battler.Within weeks of a stroke, new blood vessels begin to form, and, like marchingants, newly born neurons migrate long distances to the damaged area to aid theregeneration process. What is not known, however, is what cellular environmentand what cellular cues are necessary for this process of regeneration andmigration to take place.

Now, in the Journal ofNeuroscience currently online, Dr. S. Thomas Carmichael, assistant professor inthe neurology department at the David Geffen School of Medicine at UCLA, andhis colleagues report that in a mouse model, this neuron march is the directresult of signaling from the newly blooming blood vessels, thus causallylinking angiogenesis — the development of new blood vessels — and neurogenesis,the birth of new neurons. Further, they have identified what these molecularsignals are. The results hold promise for eventual clinical applications thatmay spur brain repair after stroke.

Stroke is the leading causeof adult disability, Carmichael said. Andwhile much is known about the mechanisms of cell death in stroke, little isknown about the mechanisms of neurological recovery after a stroke. Carmichael's lab studies the mechanisms of brain repairand the recovery of function after stroke.

Recent research has revealedthat in the adult brain, new neurons form in a region of the forebrain known as the subventricular zone. Afterinitiating strokes in mice in a part of the brain located far from this region,Carmichael and his colleagues used a combination of mitotic, genetic and virallabeling to track newly formed "neuroblasts" — immature brain cells from whichmature adult neurons form — as they traveled from the subventricular zonethrough healthy brain tissue to the stroke area. Once there, these immatureneurons wrapped themselves around the immature vascular cells that were in theprocess of forming new blood vessels in the damaged area. The neurons werefound to arrive at the site within the first two to four weeks after thestroke.

Further, the researchersfound that two proteins — stromal-derived factor 1 (SDF1) and angiopoietin 1(Ang1) — given off by these newly-forming blood vessels are what trigger themigration of thousands of immature neurons to the site of damage.

"The SDF1 and Ang1 proteins are what link the twoprocesses of neurogenesis and angiogenesis together, by promoting post-strokeneuroblast migration," Carmichael said.

They also appear to effect behavioral recovery aswell, he said. When researchers produced stroke in an area of the brain thatcontrols a mouse's facial whiskers and then infused the mouse with Ang1 andSDF1, the function of the whiskers improved to the same level seen in thecontrol (non-stroke) group of mice.

If harnessed properly, said Carmichael, the molecular mechanisms for neuronalregeneration hold the promise of regenerating and reconnecting brain cells nearthe area where stroke occurs. While the process may vary between mice andhumans, he said, it's known that neurogenesis occurs in humans.

"We're hopeful that we cantake advantage of the brain's plasticity," Carmichaelsaid. "This work could lead to the development of new therapies that willpromote brain repair after stroke."

Other authors of the paper were John J. Ohab, SheilaFleming and Amin Blesch. The research was supported by a grant from theAmerican Heart Association and a Distinguished Scholar Award from the Larry L.Hillblom Foundation.

The UCLA Department ofNeurology encompasses more than a dozen research, clinical and teachingprograms. These programs cover brain mapping and neuroimaging, movementdisorders, Alzheimer's disease, multiple sclerosis, neurogenetics, nerve andmuscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology,headaches and migraines, neurorehabilitation, and neurovascular disorders. Thedepartment ranked No. 1 in 2005 among its peers nationwide in NationalInstitutes of Health funding. For more information, see http://neurology.medsch.ucla.edu/.

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