As the "decade of the brain" draws to a close, the human brain continues to be one of the great frontiers of modern science, as full of tantalizing questions and baffling puzzles as the depths of interstellar space.
Despite its complexity and depth, though, the brain has very modest beginnings.
"In the developing fetus, the brain essentially starts out as a bag of undifferentiated cells," says Anirvan Ghosh, an assistant professor of neuroscience. "They're just basically dividing and occupying the space where the brain will be."
Ghosh studies factors and processes that shepherd the brain's transformation from a humble, growing sack of cells into a specialized information-processing structure. His research is focused on the cerebral cortex, the area where many of the brain's most advanced functions are performed.
Ghosh's efforts and insights recently won him a Presidential Early Career Award for Scientists and Engineers, the nation's highest honor for young researchers. He will receive up to $500,000 over five years to further his research.
"I regard Anirvan as one of the most talented, if not the very most talented, young developmental neurobiologists in America," says Solomon Snyder, Distinguished Service Professor and director of Neuroscience. "He is unique in that he combines powerful expertise in molecular biology and in more systems-oriented neurobiology, looking at the brain from both microscopic and macroscopic perspectives."
Ghosh has a bachelor's degree in physics and a Ph.D. in developmental neurobiology, and he served his postdoctoral fellowship with a distinguished molecular biologist. It is this variety of experiences, Snyder notes, that is the secret of Ghosh's "extraordinary success at making major discoveries" in brain development.
Both genetic and environmental influences guide brain development, and Ghosh is studying aspects of each. He has developed a laboratory model of nerve cell development that lets him apply different stimuli, typically chemical signals, to a developing nerve cell and observe the resulting effects.
"Our first major area of interest is the transition that causes the cells of the early brain to stop dividing and take on the specialized characteristics of nerve cells," Ghosh says. "None of the cells in the brain area are doing anything but dividing up to a certain point, but then they stop dividing, change into nerve cells and start making the connections with each other that allow them to process information. We want to identify the molecules that regulate this transition."
Ghosh's group has found evidence that two families of proteins, known as Notch and Rho, are signaling molecules involved in the switch that starts brain construction.
To learn more about the role of these and other similar molecules, he is working to "misexpress" the genes for the molecules in his lab model, creating developing nerve cells with abnormal levels of the signals. His team is also actively searching for other molecular signals that help regulate the switching process.
His results may help researchers develop new methods to test for developmental disorders like microencephaly or lissencephaly, where problems in the early stages of brain development produce a much smaller or a superficially smoother brain.
"It's not clear what causes these problems, but a defect in the transition from undifferentiated cell to nerve cell seems to be involved," Ghosh explains.
Once the new nerve cells of the brain start making connections with each other, some connections are used frequently and are strengthened, while others are used less often and eventually die out.
This process of creating and pruning nerve cell connections continues throughout life but is particularly pronounced in newborns and infants. "We believe this process, called plasticity, is one of the primary ways environmental stimuli are translated into biochemical changes in the brain that allow it to learn things," Ghosh says.
Ghosh's group found a connection between the creation of brain-derived neurotrophic factor, which stimulates nerve cell growth, and times when a nerve cell is in use.
"One way nerve cells receive signals involves opening up a passageway on their surfaces for electrically charged calcium atoms," Ghosh explains. "We found that when these calcium channels are opened, the cell starts making a template that is the first stage for making the BDNF protein."
Ghosh is currently working to determine the biochemical connections between the channel and the BDNF template.
Fully detailing this connection could help scientists seek new ways to treat learning disorders, he notes. "We think a number of subtle and not-so-subtle learning deficits may result from problems in nerve connectivity, so the more we can learn about it, the better our chances of developing a way to treat these disorders."