Duke Researchers Discover New Molecular Pathway for Sculpting Brain Circuits
DURHAM, N.C. -- Nerve growth factors are more than just a kind of elixir for the brain, as is now thought, according to findings by neuroscientists from Duke University Medical Center. Instead, growth factors actually oppose one another in some cases, shaping neural networks in the brain in response to experience and learning.
The studies, featured as the cover story in the May issue of the journal Neuron, show for the first time that nerve growth factors are antagonistic to one another in the brain.
"This is the first inkling we've had that nerve growth factors are not simply growth promoters," said Donald C. Lo, the study's lead author. "Instead, it appears growth factors sculpt individual neural pathways in the brain for different purposes. This represents a dramatic shift in the way we think about how brain pathways are shaped."
The studies, conducted by Lo, assistant professor of neurobiology; A. Kimberley McAllister, a neurobiology research assistant; and Lawrence C. Katz, a Howard Hughes Medical Institute investigator, provide a molecular explanation for how brain circuits are molded in response to learning and experience, since the growth factors stimulate or repress growth in response to electrical signals triggered by environmental stimulants.
"The dominant school of thought about brain development is that we are born with more than twice as many neurons as we need and the ones we don't use are slowly whittled down as the developing brain matures," Katz said. "We've shown neurotrophins do much more than simply keep brain cells alive. They instruct different aspects of nerve cell growth in different portions of the brain, and their roles change depending on their location."
In addition, the findings have implications in development of therapies for neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease and Alzheimer's disease.
The research was funded by a Ruth K. Broad Biomedical Research Foundation Fellowship to McAllister, the Alfred P. Sloan Foundation, the McKnight Endowment Fund for Neuroscience, and grants from the National Institutes of Health.
The four known human nerve growth factors are known in the aggregate as neurotrophins. The first, nerve growth factor (NGF), was discovered by in 1951 by Rita Levi Montalcini, then of Washington University in St. Louis. She won the Nobel Prize in Medicine in 1986 for its discovery. The others, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4) were discovered in the last decade.
Previous studies had shown that individual nerve growth factors are needed by different types of nerves in the body to survive. But the role of nerve growth factors in the central nervous system -- the brain and spinal cord -- has remained an enigma.
Nerve growth factors have been thought simply to maintain remaining neurons in the brain and perhaps direct growth of some neural connections. Several research teams had shown that different growth factors are produced in different layers of the cerebral cortex, the portion of the brain responsible for "higher" brain functions such as sight, language and learning, but no one knew what their roles might be.
Katz, Lo and their colleagues used slices of ferret visual cortex to study the effect of neurotrophin levels on growth of nerve cells. They applied proteins that neutralize the effects of each neurotrophin to see how growth was affected. They found that in one slice of the visual cortex, called layer 4, BDNF promotes growth of new nerve outgrowths called dendrites, which form new connections with other neurons. In contrast, NT-3 neutralized the effect of BDNF, stopping new dendrite growth. But in layer 6, the effects were reversed. NT-3 promoted growth, while BDNF stopped growth.
The research builds on previous work by the Duke team showing that neurotrophins promote nerve growth only in neurons that are stimulated by activity provided by the environment. In the December 1996 issue of Neuron, the researchers showed BDNF enhanced growth of nerve connections only when the nerve cells were active.
In addition, previous studies had relied on adding purified growth factors to cells and measuring growth. Katz, Lo and their colleagues instead blocked growth factors already in cells and measured the effect on remaining growth factors made within the brain. The Duke team showed for the first time that growth factors made in the brain play a direct role in shaping how new nerve connections form in response to a stimulus, such as a new learning experience.
"It has not been possible to do these types of studies until recently," Katz said. "The availability of nerve growth factor neutralizing proteins has made it possible to study the effects of nerve growth factors in living brain tissue."