Researchers Continue to Debate Adult Neurogenesis

Perhaps one of the most energetic debates in modern neuroscience is whether the adult human brain can create new neurons. For much of the 20th century, it was believed that neurogenesis (the birth of new neurons) stopped shortly after birth—what you brought into the world was what you had to work with. Starting in the 1980s, however, researchers found solid evidence that new neurons continued to form and grow in some brain regions in many adult animals, including in humans.

One of the regions where neurogenesis appears to occur in adulthood is in the hippocampus—the brain’s center of learning and memory. The researchers assumed that if the adult brain can continue to create new neurons in this region, there may be opportunities to exploit this process to treat neurological disorders such as Alzheimer’s disease.

As research evidence grew, however, so did conflicting data as to how many new brain cells are generated in the hippocampus during adulthood and at what point the formation of new cells stops. That conflict was well framed this past spring, when a pair of high-profile studies that used advanced neuroimaging approaches were published within weeks of each other—one reported that neurogenesis continues to occur in people aged 70 and older, while the other concluded that few new neurons are formed after a person reaches adolescence.

Daughter Cells Last a Lifetime

Maura Boldrini, M.D., Ph.D., a research scientist in the Department of Psychiatry at Columbia University Medical Center, led the efforts on the former project demonstrating adult neurogenesis. The study, which was published in Cell Stem Cell, suggests that the human hippocampus has a finite number of true progenitor cells—stem cells that can mature into any other cell type found in the brain.

These progenitors are normally quiescent, but when new neurons are needed, they wake up and make daughter cells, depleting the progenitor pool in the process, Boldrini’s group showed.

“This finite pool is normally enough to last a lifetime, though, so you shouldn’t worry that it gets smaller over time,” Boldrini said.

The daughter cells—which are not as pluripotent as the progenitors but can still mature into a range of neurons—remain active and at fairly constant levels throughout life, localized in a hippocampal region known as the dentate gyrus. Boldrini pointed out that the dentate gyrus contains millions of neurons and only a few thousand daughter stem cells; new neurons represent a tiny fraction of the total cells in this area.

The brain tissue that Boldrini’s team used came from healthy individuals aged 14 through 79, she explained. “We don’t yet know how stem cell proliferation may be altered in Alzheimer’s or other neurological disorders,” Boldrini said.

New Cells Undetectable in Adults

Across the country, Arturo Alvarez-Buylla, Ph.D., the Heather and Melanie Muss Professor of Neurological Surgery at the University of California, San Francisco, and his lab have painted a different portrait of neurogenesis in adults. Their work suggests that neurogenesis in the hippocampus is prolific in fetuses and infants, but then drops rapidly during adolescence and becomes almost undetectable in adults.

Unlike Boldrini’s group, which included only healthy samples, the brain samples that Alvarez-Buylla analyzed included those from people who had epilepsy. He doesn’t think that was a significant factor in not finding any evidence of adult neurogenesis; samples from children with epilepsy showed the same levels of stem cell proliferation as children who did not have epilepsy.

“By no means would I state that there is no adult neurogenesis in the human hippocampus,” Alvarez-Buylla said. “It may occur at levels that we cannot detect yet, or maybe it is higher in some rare individuals. But if it is that rare, the question becomes, how much does neurogenesis contribute to learning and memory in adults?”

All Studies Have Caveats

When asked about why Boldrini’s group was able to detect neurogenesis in adults, Alvarez-Buylla said he thinks that the staining procedure used by Boldrini and colleagues may have inadvertently captured some brain cells that were proliferating, such as glia or astrocytes, but weren’t new neurons. “The cells [in the images of their paper] don’t have the classical features that young neurons should have,” he said.

The other eyebrow-raising aspect Alvarez-Buylla noted in Boldrini’s findings was that neurogenesis was not reduced in older samples, even in people over 70 years. “This hasn’t been observed in any species that I know,” he said. “Even when neurogenesis does occur in adult animals, it slows down with age. However, all studies have caveats, our study had some caveats as well.”

One notable limitation of Alvarez-Buylla’s study is that the brain samples used in his study were collected from multiple sources, and not just one central brain bank. Therefore, his samples might have been preserved using different methods, which could affect the quality of the samples for molecular imaging. Boldrini also pointed out that Alvarez-Buylla and his lab did not have access to the whole dentate gyrus, just millimeter-length samples of a region that is about four centimeters long.

“Our work indicated that stem cell proliferation is not homogenous throughout the dentate gyrus; some areas are prolific and others barren,” Boldrini said. “Small samples may not tell the whole story.”

Boldrini added in defense of her own study that while proliferation remained high in older adults, the fresh neurons produced in older individuals were less able to make spiky protrusions known as dendrites, which are used to connect with other neurons. She said this difference may represent the changes in neurogenesis that come with age. She acknowledged that her group looked at brain samples only from people aged 14 and older. Therefore, she could not form a definite conclusion on how neurogenesis changes over the lifespan.

Why Such Different Findings?

Hongjun Song, Ph.D., a professor of neuroscience at the University of Pennsylvania Perelman School of Medicine, told Psychiatric News that the differing findings of these two similar studies highlight the key bottleneck in neurogenesis research.

“We don’t really know how to look for stem cells in the adult brain,” he said. According to Song, researchers who use imaging techniques to study neurogenesis rely on the same handful of proteins associated with stem cells when determining whether a cell is a stem cell. The researchers apply special molecular probes to these proteins that make them light up when viewed under a microscope. If the stem cell proteins are present, researchers consider the cell in question to be a stem cell.

The proteins currently used to assess stem cells were selected because they light up very well in animals and fetal tissue, Song explained. “The assumption has been that these biomarkers must work in adult human samples too, but maybe they aren’t the right ones.”

Song said that rather than just look at a few protein markers, researchers should assess the expression profiles of all proteins in cells of interest; these global profiles might better differentiate mature neurons, stem cells, and other brain cells that are actively dividing but are not stem cells.

He also thinks that research needs to spend as much time on the “why” of neurogenesis as the “when” and “how much.”

“Adults have plenty of perfectly good neurons in their brains, so what do new ones do that older ones cannot?” ■