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Neurogenesis
Study Sparks Controversy Over Whether Humans Continue to Make New Neurons Throughout Life

ARTICLE IN BRIEF

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DR. ARTURO ALVAREZ-BUYLLA: “We have just looked at one region of the brain. There is a lot more work to do. Clearly the fascinating process of making a new neuron continues in young children. We should continue to study how neurons are made and whether it is possible to induce new neurons to grow in the adult brain to treat brain diseases.”

A new study offers new data challenging the prevailing view that neurogenesis occurs beyond childhood into adulthood.

For two decades, humans have been comforted by scientific discoveries showing that specific regions of the human brain, primarily the hippocampus, continue to grow neurons throughout life, a finding that suggests more is better (for learning and memory that are governed by the hippocampus) and that there may be backup plans in case our old neurons die.

But scientists at the University of California, San Francisco (UCSF) have looked at dozens of tissue samples from autopsied brains and epilepsy patients undergoing resection and found that the birth of new neurons is robust in fetal life and during the first year of life but then decreases rapidly in childhood. In adults, it was not possible (with current technology used) to identify populations of new neurons. The oldest samples with evidence of neurogenesis came from seven-year-old and a thirteen-year-old, the researchers reported in the March 15 issue of Nature.

Until the late 1990s, it had long been thought that primates, including humans, are born with the complete set of neurons for a lifetime. Through development and beyond, humans lose neuronal cells, but never gain new ones. First came rodent and bird studies, then monkeys, refuting these age-old beliefs, and then evidence from humans as well.

In an editorial in the same issue of Nature, neuroscientist Jason Snyder, a doctoral candidate and assistant professor in the psychology department at the University of British Columbia, wrote that the findings “are in stark contrast to the prevailing view” and “certain to stir up controversy.”

The study was led by Arturo Alvarez-Buylla, PhD, the Heather and Melanie Muss professor of neurological surgery at the University of California, San Francisco. Dr. Alvarez-Buylla was at Rockefeller University in the 1980s working with his mentor, Fernando Nottebohm, PhD, who first reported the birth of new neurons in the brains of adult canaries and its possible link to learning their annual mating songs. Dr. Alvarez-Buylla has spent his career studying the mechanism of adult neurogenesis and began looking at human samples more than a decade ago.

“We find that neurogenesis in the adult hippocampus in humans, if it occurs at all, is an extremely rare phenomenon, raising questions about its contribution to brain repair or normal brain function,” said the neuroscientist. “We have just looked at one region of the brain. There is a lot more work to do. Clearly the fascinating process of making a new neuron continues in young children. We should continue to study how neurons are made and whether it is possible to induce new neurons to grow in the adult brain to treat brain diseases.”

STUDY METHODS, FINDINGS

Dr. Alvarez-Buylla and his colleagues studied 59 samples of human hippocampal tissue from UCSF and collaborating centers around the world. Thirty-seven came from postmortem brain samples and the rest were from fresh tissue excised from patients undergoing treatment for epilepsy. The samples came from fetuses, newborns, children, adolescents and adults. The oldest sample came from a 77-year-old.

The investigators used several techniques to tag neural stem cells and young neurons (the markers include doublecortin and PSA NCAM) to search for evidence of newborn and mature brain cells. They also used high resolution electron microscopy to examine the cell's shape and structure to make sure they were looking at neurons and not glial cells.

Dr. Alvarez-Buylla and his colleagues found evidence of new neurons in the dentate gyrus of the hippocampus in the fetal brain tissue and in the samples from newborns and infants. They counted an average of 1,618 young neurons per square millimeter of brain tissue at birth. The older the infant, the fewer the new neurons. The tissue from one-year olds have five-fold fewer new neurons; there was a 23-fold decline by age seven, and new neurons were hard to find by adolescence. The teen brain had about 2.4 new cells per square millimeter of dentate gyrus tissue.

The investigators did find an occasional young neuron in a few adult post-mortem brain samples in the walls of the brain ventricles, as previously reported, but when looking at the hippocampus of samples from people over 18 years old, the group could not find the young neurons or much evidence of proliferation next to the dentate gyrus, said Dr. Alvarez-Buylla.

The group also looked for neural progenitor stem cells that give rise to neurons. Again, it was not surprising that the fetal brain was filled with these progenitors, particularly in regions were the dentate is growing, but these cells were gone by early childhood, he explained.

Dr. Alvarez-Buylla said that the idea for this study was sparked by a visit to the laboratory Zhengang Yang, PhD, at Fudan University in China and co-author on the current paper.

Dr. Yang showed him some beautifully stained samples of hippocampal tissue from a 35-year-old. The tissue was collected within hours of his death. “We could find some new neurons close to the walls of the ventricle, but not in the hippocampus,” said Dr. Alvarez-Buylla. That was four years ago.

Dr. Alvarez Buylla returned to California and started looking at more hippocampal tissue in samples collected at UCSF. Then, he and his colleagues looked at more tissue samples from Jose Manuel Garcia-Verdugo, PhD, of University of Valencia in Spain and from Gary W. Mathern, MD, from the University of California, Los Angeles, also study collaborators.

“We are simply reporting what we observed, and to correct the record that there is no significant neurogenesis in the adult human hippocampus,” Dr. Alvarez-Buylla said.

“The process of making a new neuron in the adult brain remains a fundamental problem that we need to understand,” added Dr. Alvarez-Buylla, who is co-founder of Neurona Therapeutics, and serves on its scientific advisory board. “What's next is to do more research.”

He thinks that the replacement of neurons in the complex human brain could potentially change brain circuits in detrimental ways. “Neurons have the potential to live for very long periods of time. There may be important reasons why we may need to keep the neurons we develop in fetal and early postnatal development.

There could be other reasons, he explained: “Making a new neuron in large brains, like ours, may be complicated by the changes in development. We have speculated that the early specification of stem cells (that is linked to location) could make it very difficult to seed stem cells within niches that continually expand to incredibly large sizes. It could also be associated to longevity; stem cells may not be able to self-renew infinitively and in species that live as long as we do, these key progenitors may get used up in early life. We, simply, do not know why some species retain significant neurogenesis in adulthood, while others, like us don't.”

He also stressed that this study focused only in the hippocampus and in the search for the new neurons in the dentate. “There is a lot of human brain yet to be explored.”

“I think that we need to step back and ask what that means,” added UCSF neuroscientist Shawn F. Sorrells, PhD, the first author of the Nature paper. “If neurogenesis is so rare that we can't detect it, can it really be playing a major role in plasticity or learning and memory in the hippocampus?”

EXPERT COMMENTARY

No one refutes the science that rodents continue to grow neurons throughout adulthood and that these neurons migrate to specialized regions like the dentate gyrus and the olfactory bulb. Elizabeth Gould, PhD, a neuroscientist at Princeton University, described neurogenesis in the dentate gyrus of adult rats in 1992. Fred H. Gage, PhD, a neurobiologist in the laboratory of genetics at The Salk Institute for Biological Sciences, published a series of studies suggesting that enriched environments and exercise could enhance adult neurogenesis in rats. Others showed that stress could diminish it.

Dr. Gage and his colleagues reported the first evidence of adult human neurogenesis in tissue samples from five cancer patients in 1997. Cancer doctors had used an imaging stain called bomodeoxyuridine (BrdU) in their patients to track tumor growth, and the scientists received permission to obtain brain slices right after the patients died. BrdU gets into the DNA of dividing cells, and the Salk scientists found staining in the dentate, which suggested that these were new neurons.

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DR. DAVID R. KORNACK: “The strength of the finding is that they did see new neurons in younger tissue and not in older tissue. It confirms that hippocampal neurogenesis declines with age, which was already shown in monkeys and rodents. We are a long-lived species that rely on stored memories and behavior for our survival and stability. It may be a disadvantage to replace old neurons.”

The science of adult neurogenesis continued to be debated as researchers questioned how robust the cellular growth is, where it is, and, most importantly, what is the purpose of this proliferation.

This new study may fuel this controversy. “This paper is the most thorough and rigorous study to date addressing human hippocampal neurogenesis,” said David R. Kornack, PhD, associate professor in the department of neuroscience at the University of Rochester. “It is such an important issue whether we continue to make new neurons in our brains as adults that the evidence has to be incontrovertible.”

Dr. Kornack has been studying neurogenesis for decades and was working with Pasko Rakic, MD, PhD, at Yale University School of Medicine, in the late 1990s when they identified evidence of adult neurogenesis in macaque monkeys — in a confocal microscope, they saw what they believed to be a small population of new neurons in the dentate gyrus of the hippocampus.

They published the study in 1999 in the Proceedings of the National Academy of Sciences, and Dr. Rakic continued to raise his concerns about adult neurogenesis in humans.

“For me, this new study closes the chapter about the prevalence of hippocampal neurogenesis in human adults,” added Dr. Kornack. “We are learning the powers and limitations of the technology and defining what a new neuron is. The strength of the finding is that they did see new neurons in younger tissue and not in older tissue. It confirms that hippocampal neurogenesis declines with age, which was already shown in monkeys and rodents. We are a long-lived species that rely on stored memories and behavior for our survival and stability. It may be a disadvantage to replace old neurons.”

His mentor agrees. “I feel vindicated,” said Pasko Rakic, MD, PhD, the Dorys McConnell Duberg professor of neuroscience and professor of neurology at Yale University School of Medicine. “I wanted to discover adult human neurogenesis, but I just couldn't find it.”

Dr. Rakic said that adult neurogenesis is a limited event in the human brain, where even fewer new neurons were found than in the macaques. Additionally, he said adult rats had 10 to 14 times more new neurons in the hippocampus than the macaques had. The decreases in the number of these cells from rats to primates suggests, he said, “it must be more important not to have new neurons.”

Dr. Rakic added: “In evolution, our advantage is to preserve learned behavior. For memory, it isn't productive to have new neurons but to preserve our old ones. We need stability of our neurons. If we added new neurons, they would not hold the memories of our past experiences. I use the same neurons I did as a child when I think of my mother. We need to invest in understanding how to keep our old neurons healthy. People think this is a negative finding. I think it is positive. It shows the value of keeping old cells in our brain, cells that have accumulated a lifetime of knowledge.”

Dr. Gage, PhD, of the Salk Institute for Biological Sciences, said that this latest study doesn't disprove adult neurogenesis. Their conclusion is based “on the absence of morphological features and the lack of expression of two marker proteins, DCX and PSA-NCAM,” he said. “Both markers are very sensitive to methodological factors inherent to human brain tissue. One is the postmortem delay, the time between the death of a person and the moment the brain is removed and fixed. DCX is rapidly broken down after death and its staining disappears within a few hours of postmortem delay.”

He continued: “In this paper, many subjects had very long postmortem delays of ‘less than 48 hrs.’ As there is no mention of matching between subjects, or other optimization done in terms of the markers used, this influence of postmortem delay and on DCX integrity, which will also differ strongly between subjects, would question their conclusion about neurogenesis, as no control for DCX degradation was included.”

He added that adult mouse and adult human neurogenesis may use different proteins and they did not quantify or measure adult neurogenesis but rather proteins expressed in mice and immature cells.

LINK UP FOR MORE INFORMATION:

•. Sorrells SF, Paredes MR, Cebrian-Silla A, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults https://www.nature.com/articles/nature25975. Nature 2018; 555(7696): 377–381.
•. Snyder JS. Questioning human neurogenesis https://www.nature.com/articles/d41586-018-02629-3. Nature 2018; 555(7696):315–316.
•. Kornack DR, Rakic P. Continuation of neurogenesis in the hippocampus of the adult macaque monkey http://www.pnas.org/content/96/10/5768. Proc Natl Acad Sci USA 1999; 96(10):5768–5773.