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Neurons generated in the adult brain learn to respond to novel stimuli
MGH study finds first function for, promising flexibility in adult-born nerve cells

BOSTON - November 15, 2005 - New brain cells that develop in the olfactory system of adult mice appear to play a role in the brain different from that of older neurons. The new olfactory neurons are especially sensitive to novel stimuli, preferentially learning to respond to new odors. This level of flexibility suggests that such newly-generated neurons could be induced to adapt to and integrate into other regions of the brain, perhaps allowing them to replace neurons lost to injury or disease. The report from researchers at the Massachusetts General Hospital (MGH)-Harvard Medical School (HMS) Center for Nervous System Repair (CNSR) appears in the Nov. 16 Journal of Neuroscience.

"Our results show that these new neurons have a lot of plasticity and can contribute to important learning and memory functions of the brain, suggesting that similar, newly recruited neurons may be able to function in other parts of the brain," says Sanjay Magavi, PhD, who led the study as a fellow in the laboratory of Jeffrey Macklis, MD, DHST, director of the MGH-HMS CNSR. "Eventually we'd like to be able to redirect brain cell precursors or stem cells to make other types of neurons in regions of the brain that do not normally regenerate." Magavi is now a postdoctoral fellow at Massachusetts Institute of Technology.

It had long been believed that neurons, the active cells of the brain and nervous system, do not regenerate. Recent research has shown, however, that new cells are added to certain areas of the brain - including those involved with memory and the sense of smell - well into adulthood. Very recent work, in particular a number of studies from the MGH-HMS CNSR team, shows that neural precursors/stem cells can be induced to form some of the much more complex neurons in the cerebral cortex, the brain's highest-level structure. The current study was designed to investigate whether newly generated olfactory neurons simply replace older neurons or play a distinct role in learning and memory.

The investigators used two groups of mice whose precursor cells had been labeled to mark those that were dividing, allowing identification of newly generated, adult-born neurons. These mice were then exposed either to a panel of unusual odors or to a normal environment. Several weeks later, the response of the adult-born neurons was evaluated by measuring the activity of genes known to be expressed when olfactory neurons respond to odors.

They found that the adult-born olfactory neurons of mice exposed to the panel of odors subsequently responded more strongly to those odors than did adult-born neurons of mice that had no experience with the odors. The findings suggest that the new cells specialize in detecting previously unencountered odors and in subsequently responding to those smells.

"These contrasting responses suggest that adult-born olfactory neurons have a unique role in the brain, becoming linked to new smells while the older neurons essentially step out of the way. And since adult-born neurons are continually being generated, there is always a group of new cells waiting to link up with new stimuli," Macklis says. "We're also seeing how the environment can alter adult-born neurons and how experience and activity are important for making sure new cells integrate properly."

An associate professor of Surgery at Harvard Medical School, Macklis also notes, "These results can contribute to our efforts, and those of others in the field, to repair diseased brain and spinal cord by directed development of specific neurons from precursor/stem cells. Our experiments show that new neurons can join brain circuits and function in complex ways - contributing to learning, memory and potentially to motor function - and that we may need to retrain the brain to use the new neurons effectively."

Along with Macklis, the study's principal investigator, the paper's co-authors are Bartley Mitchell, PhD, Oscar Szentirmai, MD, and Bob Carter, MD, PhD, all of the MGH-HMS CNSR. The work was supported by grants from the National Institutes of Health, including a Jacob Javits Investigator Award from the National Institute for Neurological Disease and Stroke; the Leopold Schepp Foundation; the LifeBridge Foundation; and the United Sydney Association.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.

Media Contact: Sue McGreevey, MGH Public Affairs

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