Oct. 15, 1999 Finding reverses long-held beliefs and has implications for designing therapies
PRINCETON, N.J. -- In a finding that eventually could lead to new methods for treating brain diseases and injuries, Princeton scientists have shown that new neurons are continually added to the cerebral cortex of adult monkeys. The discovery reverses a dogma nearly a century old and suggests entirely new ways of explaining how the mind accomplishes its basic functions, from problem solving to learning and memory.
Elizabeth Gould and Charles Gross report in the Oct. 15 issue of Science that the formation of new neurons or nerve cells -- neurogenesis -- takes place in several regions of the cerebral cortex that are crucial for cognitive and perceptual functions. The cerebral cortex is the most complex region of the brain and is responsible for highest-level decision making and for recognizing and learning about the world. The results strongly imply that the same process occurs in humans, because monkeys and humans have fundamentally similar brain structures.
"This is an absolutely novel result," says William T. Greenough, director of the neuroscience program at the University of Illinois' Beckman Institute. "These data scream for a reanalysis of human brain development."
The traditional view among neuroscientists has been that the primate brain is different from other organs in that it is not capable of repairing itself or growing new cells, that no new neurons are added to the brain in maturity. This dogma has gradually eroded in the last decade as evidence accumulated for neurogenesis in several evolutionarily older parts of the brain such as the olfactory system and the hippocampus, which is believed to play role in memory formation. In the last year, Gould and her colleagues helped this erosion by proving neuro-genesis in the hippocampus of several types of monkeys.
The new finding in the cerebral cortex is much more dramatic, the Princeton team believes, because the cortex is the largest and most advanced part of the brain. After the discoveries in the hippocampus, says Gould, most scientists remained convinced that adult neurogenesis was an anomaly and could not be found in the newer, higher parts of the brain. They believed, for example, that the brain relies on a stable structure for storing memories.
"People thought: If the cerebral cortex is important in memory, how could it change?" says Gross. "In fact the opposite view is at least as plausible: if memories are formed from experiences, these experience must produce changes in the brain."
Although practical applications of the discovery could be years, even decades away, the results suggest that scientists may one day exploit natural repair mechanisms to treat brain injuries or diseases, such as Alzheimer's and Parkinson's. The Princeton scientists found that the new neurons were formed in the lining of the cerebral ventricles, large fluid-filled structures deep in the center of the brain, and then migrated considerable distances to various parts of the cerebral cortex. This type of migration, which had never been seen before, may prove useful in guiding therapeutic cells to desired sites in the brain that have lost their functioning neurons through disease or injury.
"It shows there are natural mechanisms in the brain that, someday, might be harnessed for therapeutic purposes to replenish damaged areas of the brain," says Gould. For now, that possibility remains speculative. Such work would fall to other scientists who have expertise in human diseases.
Greenough, of the Beckman Institute, says the study also has major implications for theories about how the brain develops. In particular, it casts doubt on the notion that the all-important time for brain development is from zero to three years of age, and raises the likelihood that experiences through adolescence and adulthood can affect the physical structure of the brain. "If what they have shown holds true for all primates, including humans, it means we really need to rewrite the book on brain development and the way that experience can affect the brain," says Greenough.
The Gould and Gross discovery also may require neuroscientists to draw a less bold distinction between the brains of humans and other animals, says Fernando Nottebohm of Rockefeller University. Scientists have observed neurogenesis in birds and rats for many years, but assumed that as evolution advanced and mental capacities increased, the brain supported less and less neurogenesis. "What you can say now is that the primate brain is more like that of songbirds," says Nottebohm, who believes that theories of the brain have been too "human-centric."
"It is a very interesting paper," Nottebohm says. "And I think it will do the field a great deal of good."
For their experiments, Gould and Gross took advantage of the unique properties of a chemical known as BrdU. When cells are exposed to BrdU during cell division, the chemical becomes incorporated into the DNA of newly formed cells. The researchers injected BrdU into rhesus monkeys, whose brain structure is fundamentally similar to that of humans. Then, at intervals ranging from two hours to seven weeks, they looked for evidence of the chemical in neurons in the cerebral cortex. In all cases, there were neurons with BrdU in their DNA, which showed that those cells had to have been formed after the BrdU injection.
The earliest cells, found in the walls of the ventricles and then migrating toward the cortex, were not yet mature. By the time they reached the neocortex -- a matter of days -- they had developed into mature neurons. In a final test, the researchers showed that the cells extended axons, the long, thin extensions of neurons that send messages to other neurons. They injected a chemical tracer into the brains of several of the animals a few weeks after the BrdU injections. The tracer has the property of traveling from the end of an axon back to the body of the neuron. An examination of the animals' brains showed neurons that had both labels, the BrdU and the tracer, suggesting that the new cells had formed working axons and were participating in the functional circuitry of the brain.
Within the cerebral cortex, the researchers found neurogenesis in three areas: 1) the prefrontal region, which controls executive decision making and short-term memory; 2) the inferior temporal region, which plays a crucial role in the visual recognition of objects and faces, and 3) the posterior parietal region, which is important for the representation of objects in space.
Interestingly, there was no sign of neurogenesis in a fourth area, the striate cortex, which handles the initial, and more rudimentary, steps of visual processing. That contrast suggests that neurogenesis may play a role in performing higher brain functions. Virtually all theories of learning and memory hold that memories are formed by modifications at the synapse, which is the transmission junction between neurons. On the basis of the new findings, it is now conceivable that the introduction of new neurons into the circuitry of the brain may play a role in memory.
Gould and Gross emphasize that any ideas about the functions of the new neurons are highly speculative. But the fact that there is neurogenesis in the cognitive and executive portions of the brain opens vast new areas that can be explored.
Gould and Gross, both faculty members in the Department of Psychology, collaborated with graduate student Alison Reeves and research staff member Michael Graziano. The work was supported by grants from the National Institutes of Health and the James S. McDonnell Foundation.
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