A lively debate about brain's capacity for renewal

Neurogenesis, an arcane and complex issue, has leaped out of scientific journals and conferences in the last few years to land in the pages of newspapers and magazines, including Newsweek and The New Yorker.

The source of this growing interest is an ongoing debate over the brain’s ability to generate new neurons in the cortex. Pasko Rakic, M.D., Ph.D., the Dorys McConnell Duberg Professor of Neuroscience and chair of the Department of Neurobiology, believes that the neocortex of primates, including humans, gets its lifetime share of neurons during development and shortly after birth.

Elizabeth Gould, Ph.D., a professor of psychology at Princeton, has published studies asserting that primates generate neurons in the neocortex well into adulthood.

The two camps have reached such different conclusions using largely the same experimental design, but with variations in their techniques and criteria for identifying new cells. Each publication on the topic rekindles the debate.

Rakic fired the latest salvo in the December 7 issue of Science when, with colleague David R. Kornack, Ph.D., his former postdoc who is now at the University of Rochester, he reported that Gould had indeed found new cells in the neocortex. They simply weren’t neurons. Instead, reports Rakic, Gould mistook glial and endothelial cells for neurons.

“Our study shows that neurons of the cerebral cortex are created in a precise sequence during restricted periods of development before birth and during the neonatal period,“ Rakic said. “Therefore we have to live our entire lives with the cortical neurons we are born with.”

With a preponderance of evidence in its favor, this view has dominated study of the brain since the 1980s, when Rakic published his findings after conducting lengthy studies of macaque monkeys. Subsequent studies with new labeling techniques found evidence of neurogenesis in other parts of the mammalian brain—the hippocampus and the olfactory bulb. But neurogenesis in the neocortex remains a controversial topic.

Gould insists she has found new neurons in the cortex. Like Rakic, she used the thymidine analog BrdU, along with other markers that would stain new cells. And she said she has factored in the possibility of false positives. When viewed through a confocal microscope and rotated, she said, it’s clear that the cells she found are neurons. Rakic counters that BrdU labeling, although essential to identify new cells, is not by itself sufficient evidence. “Incorporation of BrdU may also occur during DNA repair, cell degeneration and during cell death,” he said. And large and multiple injections of BrdU may also induce DNA synthesis, he said.

“There are lots of reasons there could be a discrepancy in the findings,” Gould said. “We don’t go about it in the same way. Our histological techniques differ. Our animals could have different experiences.” Stress, for example, limits production of neurons, while a stimulating environment encourages it, she said.

It is also unclear what function, if any, the new neurons may have in the neocortex. Gould notes that the cortex, which is associated with higher functions, is very large. The number of new neurons she has found is so small relative to the total number that their impact may be minimal. Indeed, she said, the generation of new neurons might be a vestige of a developmental process that was never turned off.

But what Gould sees as a very small number is, to Rakic, “staggering.” To accommodate these new neurons, Rakic said, the brain would have to grow or kill off existing neurons. Rakic said he has found evidence of neither.

He also believes that neurogenesis in the neocortex makes no functional or evolutionary sense. Early in their evolution humans traded the ability to grow new neurons, as seen in fish, amphibians and reptiles, for the ability to retain memory in existing neurons, he said. “We use neurons to store our life experiences and if we change neurons every season like male canaries do, then we would lose a lot of our life experiences,” Rakic said. “Neurogenesis in the neocortex could eliminate crucial, learned cognitive functions and long-term memories. We have to learn how to preserve our neurons during disease and natural aging.”