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How Nuclear Fallout Casts Doubt on Renewal of Some Adult Brain Cells

A unique form of carbon dating, made possible by the Cold War, suggests that new neurons rarely survive in the human olfactory bulb after birth



Adapted from Wikimedia Commons images

The human body is a tireless gardener, growing new cells throughout life in many organs—in the skin, blood, bones and intestines. Until the 1980s most scientists thought that brain cells were the exception: the neurons you are born with are the neurons you have for life. In the past three decades, however, researchers have discovered hints that the human brain produces new neurons after birth in two places: the hippocampus—a region important for memory—and the walls of fluid-filled cavities called ventricles, from which stem cells migrate to the olfactory bulb, a knob of brain tissue behind the eyes that processes smell. Studies have clearly demonstrated that such migration happens in mice long after birth and that human infants generate new neurons. But the evidence that similar neurogenesis persists in the adult human brain is mixed and highly contested.

A new study relying on a unique form of carbon dating suggests that neurons born during adulthood rarely if ever weave themselves into the olfactory bulb's circuitry. In other words, people—unlike other mammals—do not replenish their olfactory bulb neurons, which might be explained by how little most of us rely on our sense of smell. Although the new research casts doubt on the renewal of olfactory bulb neurons in the adult human brain, many neuroscientists are far from ready to end the debate.

In preparation for the new study, Olaf Bergmann and Jonas Frisén of the Karolinska Institute in Stockholm and their colleagues acquired 14 frozen olfactory bulbs from autopsies performed between 2005 and 2011 at the institute's Department of Forensic Medicine. To determine whether the neurons were younger than the people they came from—which would mean the cells were generated after birth—the researchers needed to isolate the cells' DNA. First, they dissolved the brain tissue into a kind of soup, which they spun at high speeds so that the dense cell bodies and nuclei containing DNA sank to the bottom of the flasks. Using Y-shaped proteins called antibodies, which were hitched to fluorescent markers, the researchers tagged nuclei from both neurons and from glia, non-neuronal brain cells. After a laser-equipped cell-sorting machine identified and separated the nuclei, the researchers isolated and purified the DNA within.

Frisén and his colleagues analyzed the DNA with a unique form of carbon dating, the technique that paleontologists use to date the fossils and remains of ancient creatures. When the U.S. and Soviet Union conducted nuclear bomb tests during the Cold War, the sparring nations doubled the amount of radioactive carbon 14 in Earth's atmosphere. After the Limited Nuclear Test Ban Treaty of 1963, atmospheric C 14 levels began to return to baseline, halving every 11 years as plants and the oceans absorbed the radioactive isotopes (a different process from radioactive decay, which halves the level of C 14 in fossils every 5,700 years). Scientists have documented this steady decline by analyzing ice cores and tree rings, assigning unique atmospheric C 14 levels to each year since 1955.

This record makes it possible to accurately date recently living cells by looking at the amount of C 14 in their DNA. When one cell splits into two—and duplicates its DNA in the process—it uses of some of the organism's current supply of carbon to make DNA's backbone. People get carbon from the animals and plants they eat and plants absorb carbon dioxide—including any C 14—from the air. Therefore, levels of C 14 in the DNA of preserved cells from a deceased organism should match the atmospheric levels of C 14 during the most recent cell division. Scientists only have the opportunity to make use of this unique form of carbon dating for a few more decades, before C 14 levels drop to baseline.

In their new study, Frisén and Bergmann found that the level of C 14 in olfactory bulb neurons from all the autopsies almost exactly matched the levels of C 14 in the atmosphere when those people were born. Their olfactory bulb neurons were as old as they were—they had never been replaced. Levels of C 14 in glial cells, however, were lower than atmospheric levels of C 14 at the time of the subjects' birth—these cells had divided after the people were born. The results appear in the May 24 issue of Neuron.

Frisén's findings do not change the fact that the human brain's ventricles are reservoirs of stem cells that can mature into neurons. Likewise, the new results do not challenge the production of new neurons in tissue lining the nasal cavity. Frisén's latest study, however, adds significant weight to evidence suggesting that the garden of cells in the human olfactory bulb rarely plants new members during adulthood—a conclusion that echoes several recent studies.

Arturo Alvarez-Buylla of the University of California, San Francisco, has detailed how neurons migrate from the ventricles to the olfactory bulb in mice. When he looked for evidence of the same cellular journey in human brains, he found that the steady stream of new neurons produced between birth and 18 months of age dries up by early adulthood. Likewise, a study in China confirmed that ventricles harbor stem cells in the human brain, but found no new neurons in the olfactory bulb. (Scientific American is part of Nature Publishing Group.)

Contrasting these negative results, a 2007 paper in Science—of which Frisén was a co-author—concluded that immature cells continue to migrate to the olfactory bulb in the adult human brain and mature into neurons. The study relied on brain tissue from people who were, for medical reasons, injected with a chemical called BrdU (bromodeoxyuridine), which closely resembles thymidine—one of the building blocks of DNA. When a cell divides, it incorporates BrdU into the newly duplicated DNA, which allows researchers to identify newborn cells. Pasko Rakic of Yale University, as well as other researchers, has questioned whether BrdU reliably tags newborn cells in adult tissues because the compound can trigger cell division and label dying cells, skewing the results. To compensate for these shortcomings, some studies on neurogenesis have coupled BrdU labeling with antibodies designed to tag proteins that only immature neurons produce. Frisén and his colleagues invented their carbon dating technique in part to overcome these frustrations.

On account of the contradictory evidence and technical challenges, many neuroscientists are not prepared to put the question of neurogenesis in the human olfactory bulb to rest. In a commentary published in Neuron alongside Frisén's new study, Jeffrey Macklis of Harvard University argues that although the new study is rigorous, it does not definitively eliminate the possibility that new neurons join the adult human olfactory bulb after birth. As Macklis points out, neurons that migrate from the ventricles to the olfactory bulb in mice, but fail to receive sufficient stimulation in the form of new smells, die. If the same thing happens in the human brain, Frisén's study would have missed it. Perhaps new neurons migrate through everyone's brains during adulthood, but only remain in the olfactory bulb's circuitry if they find themselves useful. Macklis wonders whether the 14 people in the new study aroused their noses enough to keep new neurons in the olfactory bulb alive. He suggests studying the brains of "chefs, sommeliers, perfumers, vintners, 'foodies'"—connoisseurs of fragrance.

Fred Gage of the Salk Institute for Biological Studies, who has worked extensively on neurogenesis in the human brain, thinks that the new findings make sense from an evolutionary perspective. "Animals on all fours, whose noses are right there on the track, have giant olfactory bulbs compared to humans," Gage says. "The new findings might reflect the fact we are not as olfactory dependent."

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