By Steven Reinberg
WESTPORT, Jun 23 (Reuters Health) - In mice, endogenous neural precursors can be made to differentiate into mature neurons in regions of the cortex that do not normally undergo neurogenesis, according to researchers from Harvard Medical School, Boston, Massachusetts. These results, they say, support the belief that under precisely the right conditions the adult cortex can regenerate by creating neurons in response to injury or degeneration.
"We induced the birth of new neurons in the adult cerebral cortex," lead researcher, Dr. Jeffrey D. Macklis told Reuters Health. "What we did in this experiment," he explained, "was to see if we could induce signals that would recruit the precursors, right in the brain where they are, without transplantation, to make new neurons in the cerebral cortex. And what we found was strikingly yes, in small numbers."
Dr. Macklis and colleagues induced synchronous apoptotic degeneration of corticothalamic neurons in layer VI of the anterior cortex in adult mice. Using markers for DNA replication (5-bromodeoxyuridine; BrdU) and progressive neuronal differentiation, they examined the fates of dividing cells within the cortex.
The team found that "Newly made, BrdU-positive cells expressed NeuN, a mature neuronal marker, in regions of cortex undergoing targeted neuronal death," according to the report in the June 22nd issue of Nature.
In addition, they found that Doublecortin, "a protein found only in migrating neurons" and Hu, "an early neuronal marker," were both expressed by subsets of BrdU-positive precursors. Dr. Macklis' group also says that, "Retrograde labeling from thalamus demonstrated that BrdU positive neurons can form long-distance corticothalamic connections."
Dr Macklis explained that there is a combination and sequence of molecular control signals that can direct stem cells to repair the brain from "the inside out." These signals direct the cells to migrate to exactly the right location, to differentiate into the right kind of neurons, and to survive.
In this experiment, Dr. Macklis said, they had turned on the whole program of gene expression using the relatively crude external switch of inducing the death of neurons synchronously. "But," he added, "we can also do that looking directly at a molecular level to see the signals that are being induced. We know that there is an entire sequence of signals — some of them previously known molecules and some previously unknown molecules."
Over the coming years, the team will be working to uncover what that series and combination is and also to manipulate the system with specific growth factors to try to increase the rate of new neuron production. "We think, that by increasing the number of precursors or guiding them more efficiently we can make many, many more appropriate new neurons," he said.
"I think, that in the next decade, the neurons that are affected in spinal cord injury or ALS might get a clinical benefit from this approach."
"The reason I think that spinal cord damage will be first is that a relatively small number of imperfectly, imprecisely wired neurons could make the difference between the lack of function and imperfect function, which would still be a tremendous benefit. Whereas, in diseases like Parkinson's, or Alzheimer's, or stroke, I think we are decades away, because [for those] the absolute precision of the wiring is more critical."
"We are nowhere near human application. I'm an optimist, but a conservative optimist, and I believe that we, as a field, will be able to bring this type of cellular repair to the central nervous system over the next 3 decades," he added.