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March 17, 1998 = New York Times Science Section Studies Find Brain Grows New Cells By GINA KOLATA For years, neurobiologists clung to a = fundamental truth: once animals, or people, reach adulthood, they may lose brain cells but they can never grow new ones. There were a couple of exceptions -- in birds and rats -- but the thought was that these were peculiarities of nature and not evidence of a general principle. But now, in experiments that experts call amazing, that dogma has been overturned. Scientists have found that monkeys are constantly making new brain cells in the hippocampus, an area of the brain used for forming long-term memories. Moreover, they report, the production of new cells is squelched when the animals are under extreme stress. Experts say they fully expect that humans are no different and that they, too, make new brain cells in adult life. That raises the glimmer of a possibility of eventually treating degenerative disorders like Alzheimer's or Parkinson's disease and injuries, like those resulting from stroke or trauma, by prompting the brain to grow replacement cells, researchers said. It also means that neurobiologists must re-think their notions of how the brain changes with learning or life experiences. The new study was by Dr. Elizabeth Gould of Princeton University, Dr. Bruce S. McEwen of Rockefeller University in New York and their colleagues. "It means that there is a new mechanism for changing the organization of the adult brain," said Dr. William Greenough, a psychologist at the University of Illinois at Urbana-Champaign who studies learning and memory in rats. Dr. Fred Gage, a neurobiologist at the Salk Institute in San Diego, said the implications were "fabulously interesting." The investigators, working with marmoset monkeys, added two tracer chemicals to the animals' brains: one that labeled cells that were dividing, the process that gives rise to new cells, and one that labeled mature nerve cells. Cells that were born during adult life and that grew into mature brain cells would be marked by both chemicals. With this method, the researchers looked for, and found, new cells in the animals' hippocampuses. Gould estimated that thousands of such cells were being made each day. She said she suspected other cells were dying to make room for new ones, but her study did not count numbers of dying cells. The hippocampus was particularly intriguing for another reason, Gould said. Earlier research had shown that when people are under stress, the hippocampus shrinks in size. For example, people with tumors that pour out the stress hormone cortisol have a diminished hippocampus. So do people with recurrent depression and people with postraumatic stress disorder, Gould said. It might be possible, she reasoned, that monkeys under stress might decrease their production of new brain cells in the hippocampus, making that area of the brain shrink. To test the hypothesis, Gould and her colleagues stressed monkeys by putting a male monkey who had always lived alone into a small cage where another male was living. The intruder was terrified and cowered in the cage, with a rapidly beating heart. When Gould and her colleagues examined the brains of the frightened monkeys, they found that after just one hour of this stress, the monkeys were making substantially fewer new brain cells. The study is being published today in The Proceedings of the National Academy of Sciences. As so often happens in science, the seeds for the new view of brain regeneration were sown decades ago, but were largely ignored. In the 1960s, Dr. Joseph Altman, a Purdue University scientist who is now retired, reported that rats make new brain cells throughout their lives. The cells were in the hippocampus and in the olefactory bulb, an area used to sense smells, he noted. "No one paid attention," Gould said. She attributed the reaction to researchers' biases. "People thought that there was no way that such a mechanism could exist in adult mammals," Gould explained. Twenty years later, Dr. Fernando Nottebohm, who is head of the laboratory of animal behavior at Rockefeller University, asked whether brain cells were being born in adult birds. Bird brains, he noticed, grow and shrink with the seasons, swelling when the animals need to learn new songs to attract mates and shrinking after they had bred. He wondered whether the swelling brains during breeding seasons could represent the actual growth of new brain cells. At the time, Nottebohm said, he knew nothing of Altman's work. Altman, he said, "was not being quoted in books." In a series of painstaking experiments, Nottebohm showed that birds constantly = make new brain cells and that the new cells replace old ones that die. "There was a program of constant brain rejuvenation," Nottebohm said. "Parts of the brain were no different from the liver or skin. Old cells died and new ones took their place." In 1984, Nottebohm organized a meeting in New York that he called Hope for a New Neurology. A colleague at Rockefeller, Dr. Arturo Alvarez-Buylla, recalled that Nottebohm "was pushing the idea that in the adult brain, there is no impediment to the formation of new neurons." But, Alvarez-Buylla added, "people thought that was bordering on fantasy." Nonetheless, some researchers persisted, showing in rats and mice and in tree shrews that new brain cells are born throughout life, at least in the hippocampus and olefactory bulb. Dr. Alvarez-Buylla, for example, recently found that adult mice make 5,000 to 10,000 new brain cells each hour. The brain cells that end up in the olefactory bulb are born on the walls of the ventricles, cavities in the brain that are filled with cerebrospinal fluid. They travel in "little trains of cells" to their destination, he said. Those that end up in the hippocampus are born there. But many scientists believed that monkeys and humans could not be growing new brain cells, and certainly not in a area like the hippocampus. "People believed that in order to store memories for a lifetime, you need a stable brain," Gould said. "If cells are constantly dying and new ones being produced, how would that be possible?" Gould, however, was persuaded by the findings in other species. "Why not monkeys?" she asked. Others also began seeking and finding brain regeneration in monkeys, Gage said, although Gould is the first to publish her findings. The results are "very very provocative" said Dr. Ronald McKay, the chief of the laboratory of molecular biology at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. They lead, he said, to a host of other questions. How does the rate of nerve cell regeneration change as monkeys, or people, grow old? What controls the rate? How can it respond so rapidly to stress? Nottebohm has another list of questions. One of the first imperatives is to understand why the bulk of new cells seem to be in the hippocampus. Memories are stored there for weeks or months and then, it seems, moved elsewhere in the brain where they reside permanently. So, Nottebohm said, it is possible that the hippocampus has "a space storage crunch" that would cause it to run out of room for memories if it did not kill off some cells and replace them with new ones. The findings also raise the question of whether new brain cells grow elsewhere in the brain and, if so, how to stimulate their growth when the brain is injured or needs repairs. Scientists have argued that evidence from stroke or trauma victims and people with degenerative disorders like Alzheimer's disease indicates that once brain cells are lost they = cannot be replaced. But, Nottebohm said, the = problem might be that scar tissue is interfering with the reconnection of circuits in the brain, not that new cells cannot grow. "We know that when scar tissue is left behind, it interferes with the reconstitution of circuits" in the brain, he said. Gould said Alzheimer patients retain the immature cells that grow into new hippocampus cells but lose the nerves that those cells would connect to. The result is severe memory impairment. The new work, Nottebohm said, "suggests that repair is a possibility." And even though new brain cells have been found, so far, only in the hippocampus, "it emboldens you to ask, Why not elsewhere?" he said. "It is amazing," Nottebohm said. Copyright 1998 The New York Times Company