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Fossil-Dating Strategies Suggest Neurogenesis Occurs Throughout Human Lifespan

Talan, Jamie

doi: 10.1097/01.NT.0000433501.19059.8a
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Scientists took advantage of increased atmospheric carbon-14 changes triggered by the Cold War-era above-ground nuclear bomb testing between 1955 and 1963 to date-mark cell division in human tissue, and found that neurogenesis occurs throughout the lifespan.

What began with a naïve thought — why not borrow tools from archeologists who use carbon-14 to date fossils to study cells in the adult human brain — turned into a stunning and rather surprising finding by scientists at the Karolinska Institute in Sweden. Jonas Frisén, MD, PhD, a professor of stem cell research, and his colleagues used changes in atmospheric carbon-14 levels to prove that hippocampi grow a substantial and steady number of new neurons throughout the lifespan.

The study, published June 6 in Cell, offers a new window into how the brain continues to lay down new neurons, which many now believe plays a critical role in learning, memory, and possibly the development of some neurological diseases.

The scientists took advantage of increased atmospheric carbon-14 changes triggered by the Cold War-era above-ground nuclear bomb testing between 1955 and 1963. Dr. Frisén explained that carbon-14 reacts with oxygen to form CO2, which is taken up by plants. Humans are exposed through diet. It is found in every cell in the body.

In 2005, Kirsty L. Spalding, PhD, and her colleagues at the Karolinska Institute reported in Cell that a cell dividing duplicates its chromosomes and integrates carbon-14 in the synthesized genomic DNA. “It creates a date mark in the DNA,” said Dr. Frisén, who was the senior author of that study, adding that it provides hidden clues, much like the findings from a time capsule.

The challenge, said Dr. Frisén, was to see whether they could measure carbon-14 in cells and genomic DNA. It worked. They collected human donor hippocampal cells and genomic DNA from 55 people between 19 and 92 years old and non-neuronal cells from 65 other samples. They used accelerated mass spectrometry to measure carbon-14 levels.

The investigators used a mathematical model to figure out how many new cells are born per day — and even they were surprised by their answer: 1,400. Studying hippocampal neurons in people from all stages of life enabled them to see that there is a four-fold decline of new neurons over the adult life span.

The Karolinska scientists reported that one-third of hippocampal neurons are turning over on a repeated basis. Dr. Frisén said it is “a 1.75 percent annual turnover within the renewing fraction.”

“We were surprised to see that much neurogenesis in humans,” he added.

Studies in animals suggest that neurogenesis is important for learning and memory and may well be involved in certain disease states, like depression. New neurons, according to animal studies, are called on for certain memory functions, including pattern separation, Dr. Frisén explained. Pattern separation is the ability to distinguish between separate but distinct events, like remembering where you parked your car in a garage.

Scientists have also reported neurogenesis in the olfactory bulb in animals, although the Karolinska team performed carbon-14 dating in the olfactory bulb in human donor tissue and found no evidence of neurogenesis. “We expected humans to be like other animals. This was surprising.”

He said that his team is interested in the role that neurogenesis seems to play in diseases like depression and stroke. Ultimately, it may be possible to enhance the birth of new cells to treat disease, said Dr. Frisén. “Loss of cells is a feature of many diseases so it is important to develop new ways to stimulate new cell formation.”

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Fred Gage, PhD, a professor in the laboratory of genetics and the John Adler chair for research on age-related neurodegenerative disease at the Salk Institute — who in 1998 published a seminal paper in the field that helped prove brain plasticity — said he was impressed with the use of carbon-14 dating in the study.

In his own earlier research, he studied donor tissue from brain tumor patients treated with a radioactive substance called BrdU (bromodeoxyuridine) that was used to track tumor growth. The antibody stains dividing cells, which enabled scientists to analyze what cells divided and when. They found that the dividing stem cells that incorporated the BrdU label were taken up by the neurons. The finding, published in Nature Medicine, helped prove that there is plasticity in the adult human brain. But he noted it is almost impossible to find donor patients exposed to BrdU to replicate the study. Carbon-14 dating offers a new tool, Dr. Gage said.

“The investigators found a significant amount of neurogenesis beyond the fifth decade of life,” said Dr. Gage. “It is occurring at a higher frequency and a larger percentage than anyone would have anticipated.”

He added: “It's always nice when people confirm and extend a finding using a completely different technique. I like the way it was presented. It is a very clever idea.”

“The idea of using atomic bomb blasts to trace patterns of brain cell generation is remarkable and bold, yet seems to work quite well,” said Christopher A. Walsh, MD, PhD, an investigator of the Howard Hughes Medical Institute and chief of the Division of Genetics at Boston Children's Hospital and the Buillard professor of pediatrics and neurology.

“The authors find that the human hippocampus continues to add new neurons throughout life, even in older age. You might think that new neurons budding into the brain might disrupt the memories already formed. But we must ask, do we remember old things despite these new neurons, or because of them? Do new neurons signal new memories? And does a loss of adult neurogenesis with age relate to age-related cognitive decline?”

Scott A. Small, MD, the Boris and Rose Katz professor of neurology at Columbia University College of Physicians & Surgeons and director of the Alzheimer's Disease Research Center, called the study “a truly landmark paper, both for the technology it uses and for the implications of its compelling results.”

“The paper clearly establishes that adult neurogenesis in the dentate gyrus occurs in the human brain, something that was suggested by a previous study but long and hotly debated,” he said. “There were two other observations that are worth noting. First, unlike in rodents, in which neurogenesis occurs in the olfactory bulb and the dentate gyrus, human adult neurogenesis occurs only in the dentate gyrus. Second, the scientists also found that the rate of decline in neurogenesis is much lower than they have seen in rodents. There was a four-fold decline in new neurons in people beyond the sixth decade.”

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•. Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013:153:1219–1277.
•. Spalding KL, Bhardwaj RD, Buchholz BA, et al. Retrospective birth dating of cells in humans. Cell 2005;122:133–143.
•. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:1313–1317.
© 2013 American Academy of Neurology