New Evidence Supports Adult Neurogenesis in Humans, Potentially Settling Long-Standing Debate

Genetic evidence that our brains make new neurons in adulthood may close a century-old debate

For decades, neuroscientists have wrestled with -- and regularly fought over -- a seemingly basic question about the human brain: does it make new neurons in adulthood? This process, called neurogenesis, has been documented in adult rodents, but definitive evidence in humans has remained elusive. Now, a research team has tackled this old problem with two modern tools, combining a form of artificial intelligence (AI) known as machine learning and a method of showing gene activity in single cells. In Science today, the group identifies cells in adult human brain tissue with the genetic signature of neural progenitors, the cells that can divide to create neurons. Some neuroscientists see the result as conclusive evidence that neurogenesis happens in the adult human hippocampus, the part of the brain that handles learning and memory, although the new work suggests it occurs more slowly than in a developing brain, and varies greatly between people -- some adults may not generate new neurons at all. The study authors now hope to pivot their research to studying how the process contributes to learning and memory in adulthood. "This paper will make a huge contribution to the field," says Evgenia Salta of the Netherlands Institute for Neuroscience, who studies neurogenesis but was not involved with the work. It offers a "proof of concept" that neurons are born in the adult hippocampus even as we age, she says. In the early 1900s, Santiago Ramón y Cajal, the first person to characterize the structure of neurons, proposed that brain cells are "fixed, ended, and immutable" after a person is born. Even after neuroscientists realized the brain matures and grows after birth, they thought of neurogenesis as a process confined to childhood: Stem cells become progenitors, giving rise to immature neurons that develop into the mature cells we rely on for the rest of our lives. Early rodent experiments that identified neural progenitors in adult animals were largely dismissed as irrelevant to people, as "humans are not big mice," says Gerd Kempermann, a physician at the Dresden University of Technology. But starting in the 1990s, studies emerged that challenged that assumption, labeling what appeared to be actively dividing cells in adult primates and the brains of deceased cancer patients. In 2013, using an innovative carbon-dating technique to assess the ages of neurons, neuroscientist Jonas Frisén of the Karolinska Institute (KI) published evidence suggesting neurons were generated well into adulthood in the human hippocampus. But a vocal group of neuroscientists remained unpersuaded. More recently, studies using fluorescent antibodies to label proteins in postmortem studies of adult brain tissue have yielded conflicting results. Some researchers found no markers of young neurons or their progenitors; others detected doublecortin, a protein thought to be released by immature neurons, and argued it hadn't shown up in previous work due to flawed tissue preservation methods. In the new paper, Frisén and his team rely on machine learning to identify the characteristic gene activity of young nerve cells in adult rodent brains. They sequenced the RNA strands in individual cells and analyzed the messenger RNAs (mRNAs) that represent the proteinmaking instruction produced from an active gene. Then, the group searched for similar gene activity in single-cell RNA sequencing data from human postmortem tissue. Another team pioneered that approach in a 2022 Nature paper, identifying cells with the characteristics of immature neurons in the adult human hippocampus. But those researchers could not find the immature cells' precursors, the neural progenitors -- a missing link Frisén's team aimed to discover. Researchers expect neural progenitors to be even rarer than the immature neurons they spawn. To find them, Frisén's team figured out a way to sort and isolate the cells likely to be progenitors. It could then compare their genetic features with those of both adult rodent and infant human hippocampal cells. This narrowing down of likely neural progenitors is the "major advance of the paper," says neuroscientist Hongjun Song of the University of Pennsylvania, a co-author on the 2022 study. Of roughly 300,000 human hippocampal neurons, from brain tissue of teenagers to septuagenarians, Frisén's team's algorithm identified 354 as progenitor cells. Among the genes expressed in these cells, there was no "golden ticket," Salta says -- no single active gene distinguishing a progenitor from all other cell types. Rather, the analysis revealed many markers that combined may indicate an adult neural progenitor, she says. Different human brains had widely different numbers of progenitors, Salta notes, who suggests our capacity for neurogenesis may be sensitive to many environmental or biological factors. Younger brains generally had more neural progenitors than older ones, and tissue from five of the 14 adults in the data set had no discernible neural progenitors. For those that did, it's still unclear whether progenitors arose in the adult brain or were present from infancy and are simply slow to mature, the authors note. The findings suggest the rate of new neural growth is low in adults, Frisén says, though the new study doesn't estimate a precise rate. His team's earlier work suggested roughly 700 new neurons are formed each day, which is less than 0.03% of the neurons in an adult hippocampus. Shawn Sorrells, a neuroscientist at the University of Pittsburgh, says the methods in the new study "are largely indirect and need to be validated with other approaches." Sorrells, a co-author on the antibody labeling study that found no evidence of adult neurogenesis, suggests the machine learning algorithm may have been trained to identify progenitors that give rise to non-neuronal brain cells called glia, which are known to regenerate in adulthood. Overall, the results suggest neural progenitors are likely "rare or nonexistent in most individuals," he says, and it's still possible "that the cells [the authors] identify are noise or some other cell type altogether." Ionut Dumitru, a KI postdoctoral researcher and the first author of the paper, says the progenitor cells his team used as reference expressed genes that were characteristic of neurons, not glial progenitors. Kempermann and others see the new findings as clinching the argument for adult neurogenesis. "If you look at the complete body of evidence that we have today, then we must say the debate is over," he contends. Song says "the next frontier" is to study whether differences in the rate of neurogenesis in the hippocampus contribute to issues such as the cognitive decline seen in people with Alzheimer's disease -- a finding that could point to potential therapies. Frisén, too, is eager to put the long-running debate behind. "Hopefully this doesn't create more controversy, but rather some unification."

Do we grow new brain cells as adults? The answer seems to be yes

Scientists have found evidence of new brain cells sprouting in adults - a process that many thought only occurred in children Whether or not we grow new brain cells as adults has been the subject of an ongoing and often contentious debate. Now, evidence suggests that we can. This could help answer one of neuroscience's most controversial questions and has sparked some speculation that the process could be exploited to treat conditions like depression and Alzheimer's disease. New neurons form via a process called neurogenesis in children, as well as in adult mice and macaques. This involves stem cells repeatedly giving rise to so-called progenitor cells that proliferate to form immature neurons that later become fully developed. Prior studies on human adults have identified stem cells and immature neurons in the hippocampus. This brain region, which is crucial for learning and memory, is a prime spot for neurogenesis in children and some adult animals, but progenitor cells have yet to be seen here in adult humans. "We were missing this link, and that's one of the main arguments against new neurons forming in the adult human brain," says Evgenia Salta at the Netherlands Institute for Neuroscience, who wasn't involved in the new research. To find this link, Jonas Frisén at the Karolinska Institute in Sweden and his colleagues first set about creating machine learning models that can accurately identify progenitor cells. This involved collecting hippocampus samples from six young children whose brains were donated by their parents for research when they died. The researchers trained the artificial intelligence models to identify progenitor cells based on the activity of around 10,000 genes, using data extracted from the samples. "In childhood, progenitor cells look similar to what they do in mice, so we can easily identify these," says Frisén. "[The idea is] we can take the molecular fingerprints of childhood progenitors and use that to identify these cells in adults." To put the models to the test, the team had them identify progenitor cells in hippocampus samples from young mice. The models correctly pinpointed 83 per cent of the progenitor cells and incorrectly classed another type of cell as a progenitor less than 1 per cent of the time. In another test, the models correctly predicted an almost complete absence of progenitor cells in samples of an adult human cortex, a brain region where there is no evidence to suggest neurogenesis occurs in people. "They really nicely validate their model by going from human child data, to mouse data and then adult human data," says Sandrine Thuret at King's College London. Once this validation was complete, the researchers could test if neurogenesis occurs in human adults, by using the models to pinpoint progenitor cells in the hippocampus of 14 people who were aged between 20 and 78 when they died. Crucially, they first carried out a step that increased their odds of catching progenitor cells, which prior studies suggest would be very rare in adults. The team used an antibody to select for brain cells that were dividing at the time of death, including non-neuronal cells such as immune cells and any progenitors. This helped to exclude common non-dividing neuronal cells, such as mature neurons, making it easier to find rare ones. They then fed data that related to the genetic activity from those dividing cells into the models. "They enriched for the dividing cells, this allowed them to find those very rare cells which are missed if you put all the cells in," says Hongjun Song at the University of Pennsylvania. Prior studies didn't do this, he says. The team found progenitor cells in nine donors. "In rodents, it's very well known that environmental and genetic factors affect how much neurogenesis there is, so my guess is that differences among humans is due to genetic and environmental factors as well," says Frisén. The results strongly suggest to Thuret, Song and Salta that adult neurogenesis is real. "It really helps the field make a significant step forward, because it's adding this missing link," says Salta. "Neurons really are born from cell division that is present during adulthood - that's really what this paper nails down," says Thuret. It may one day be possible to study differences in neurogenesis in adults with and without conditions that affect the brain, such as depression and Alzheimer's, says Thuret. Perhaps drugs that boost this process could lessen symptoms, she wonders. But Jon Arellano at Yale University says that even if new brain cells do form in adults, there may be too few of them to be of therapeutic use. Yet Thuret thinks this is unlikely to be a problem. "In mice we see you only need a very small amount to be important for learning [and] memory," she says.

Can adults make new brain cells? New study may finally settle one of neuroscience's greatest debates

Scientists have published strong evidence of new neurons forming in the adult human brain. (Image credit: BlackJack3D via Getty Images) Researchers say they have found clear evidence that the human brain can keep making new neurons well into adulthood, potentially settling decades of controversy. This new neuron growth, or "neurogenesis," takes place in the hippocampus, a critical part of the brain involved in learning, memory and emotions. "In short, our work puts to rest the long-standing debate about whether adult human brains can grow new neurons," co-lead study author Marta Paterlini, a researcher at the Karolinska Institute in Stockholm, told Live Science in an email. Other experts agree that the work makes a strong case for adult neurogenesis. While a single study does not constitute absolute proof, "this is strong evidence in support of the idea" that stem cells and precursors to new neurons exist and are proliferating in the adult human brain, said Dr. Rajiv Ratan, CEO of the Burke Neurological Institute at Weill Cornell Medicine, who was not involved in the study. "This is a perfect example of great science teeing up the ball for the clinical neuroscience community," he told Live Science. Related: Babies' brain activity changes dramatically before and after birth, groundbreaking study finds The researchers combined advanced techniques, including single-nucleus RNA sequencing and machine learning, to sort and examine brain tissue samples from international biobanks, they reported in a paper published July 3 in the journal Science. RNA, a cousin of DNA, reflects genes that are "switched on" inside cells, while machine learning is a type of artificial intelligence often used to crunch huge datasets. Since the 1960s, researchers have known that mice, rats and some nonhuman primates make new brain cells in the dentate gyrus, part of the hippocampus, throughout life. But getting quality brain tissue samples from adult humans is extremely challenging. "Human tissue comes from autopsies or surgeries, so how it's handled -- how long before it's fixed in preservative, which chemicals are used, how thin the slices are -- can hide those newborn cells," Paterlini said. Employing new technologies enabled the team to overcome this challenge. They analyzed more than 400,000 individual nuclei of hippocampus cells from 24 people, and in addition, looked at 10 other brains using other techniques. The brains came from people ages 0 to 78, including six children and four teens. Using two cutting-edge imaging methods, the team mapped where new cells sat in the tissue. They saw groups of dividing precursor cells sitting right next to the fully formed neurons, in the same spots where animal studies have shown that adult stem cells reside. "We didn't just see these dividing precursor cells in babies and young kids -- we also found them in teenagers and adults," Paterlini said. "These include stem cells that can renew themselves and give rise to other brain cells." The newer technologies enabled the researchers to detect the new brain cells at various stages of development and conduct research that wouldn't have been possible a few years ago, Ratan added. The team also used fluorescent tags to mark the proliferating cells. This enabled them to build a machine learning algorithm that identified the cells that they knew would turn into neurogenic stem cells, based on past rodent studies. This was a "clever approach" for tackling the challenges of studying brain-cell formation in adolescents and adults, Ratan said. As expected, the brains of children produced more new brain cells than the brains of adolescents or adults did. Meanwhile, nine out of 14 adult brains analyzed with one technique showed signs of neurogenesis, while 10 out of 10 adult brains analyzed with a second technique bore new cells. Regarding the few brains with no new cells, Paterlini said it's too soon to draw conclusions about the disparity between adult brains with evidence of new cells and those without. Next, the researchers could explore whether the adults who produced new brain cells did so in response to a neurological disease, such as Alzheimer's, or whether adult neurogenesis is a sign of good brain health, said Dr. W. Taylor Kimberly, chief of neurocritical care at Massachusetts General Brigham, who was not involved in the study. "They were able to find these needles in a haystack," Kimberly told Live Science. "Once you detect them and learn about them and understand their regulation," scientists can research how to track the precursor cells through time and see how their presence relates to disease, he said. He envisioned comparing patients who have dementia to "super agers" who are cognitively resilient in old age. If the link between neurogenesis and disease can be uncovered, perhaps that could open the door to treatments. "Although the precise therapeutic strategies in humans are still under active research," Paterlini said, "the very fact that our adult brains can sprout new neurons transforms how we think about lifelong learning, recovery from injury and the untapped potential of neural plasticity."