Does your brain produce new cells? (2023)

Here is the original draft ofa featured article I wrotePronew scientist, in adult neurogenesis in the human brain. You need to register to read the magazine version, but registration is free and only takes a minute.

I'm sitting on a long lab bench in theMRC Center for Developmental Neurobiology, View through a microscope of the hindbrain of a three-day-old chicken embryo. The egg had already been injected with bromodeoxyuridine (BrdU), a compound whose structure is similar to that of thymidine, one of the four main components of DNA, and which is incorporated into newly synthesized DNA.

The embryo was then removed, the hindbrain dissected and treated with an antibody that binds to BrdU. Now split across the top and spread out on a slide, this is how it looksDivided into eight compartments, each revealing their newborn cells with their DNA stained dark brown.

andres lumsden, director of the center, explains that each segment expresses a unique combination ofgenetic patternand that the boundaries of the segments restrict the movements of immature cells. Neurons in each segment are given a unique identity: those arising in the anterior segment fuse to form the nucleus of the fifth cranial nerve, while those further back form other cranial nerves.

At this stage of development, the nervous system is a hollow tube that runs along the back of the embryo. Its walls contain wedge-shaped cells that divide near the inner surface to produce neurons that migrate outward. This happens at different speeds along the length of the tube, creating three bulges at one end that eventually form the brain. Successive waves of migrating cells populate the developing brain to give the cortex its characteristic layered appearance. Once at the target site, they differentiate into the three main cell types of the brain (neurons, astrocytes, and oligodendrocytes) and then sprout connecting branches to form functional tissue.

fountain of eternal youth

For much of the last century, it was thought that the production of new neurons, neurogenesis, was restricted to embryonic development. “Once development is complete,” wrote Santiago Ramón y Cajal, the father of modern neuroscience, “the sources of growth … are irrevocably dry. In the adult, neural pathways are... immutable. Everything can die, nothing can die regenerated."

This became the central tenet of neuroscience, but the view began to change in the 1980s, whenfernando nottebohmof Rockefeller University published the first unambiguous evidence of adult neurogenesis in the vertebrate brain. Nottebohm showed that the brain of an adult canary undergoes seasonal changes in size. Males sing to serenade females, but the regions of the brain that produce the song drastically decrease in size after the breeding season. The following spring, they regenerate through neurogenesis to allow the male to learn new songs.

Indeed, Joseph Altman of the Massachusetts Institute of Technology reported evidence of adult neurogenesis in the hippocampus of adult rats and guinea pigs and in the cortex of cats in the 1960s, but his work was ignored and later ridiculed. “Altman started with the idea of ​​adult neurogenesis, but his data were not convincing,” says Nottebohm. "Our results showed beyond a shadow of a doubt that neurons are born in adulthood and are built into existing circuits. They broke most of the resistance to the idea."

Evidence for adult neurogenesis in mammals quickly followed. 1992,Samuel Weissand Brent Reynolds of the University of Calgary isolated neural stem cells from the brains of adult mice and showed that they can generate neurons and astrocytes when grown in a petri dish. This was confirmed byFred Gagefrom the Salk Institute. Working with several colleagues, Gage also showed that exercise and environmental enrichment increase the rate of adult neurogenesis and that the number of new cells produced decreases with age. Thousands of studies have been published and it is widely accepted that adult mouse brains continue to producenew neurons.

In all mammalian embryos, neurogenesis takes place along the neural tube. In the adult, the tube cavity has turned into brain chambers filled with cerebrospinal fluid, and neurogenesis is confined to two brain regions, each containing a niche with different types of stem cells.

The largest C-shaped niche in the walls of the lateral ventricles produces immature neurons thattravel in chains within the rostral travel current(RMS) to the olfactory bulb. Some differentiate into mature neurons that integrate into local circuits andparticipate in odor information processing🇧🇷 The other produces cells that integrate into the dentate gyrus of the hippocampus and play an important role in learning and memory. It's not clear exactly how the new cells are involved in processing information. They can replace dying cells or be added to existing circuits to provide additional information processing capabilities.

Other regions of the lateral ventricles contain dormant stem cells that can be activated after brain injury to produce new cells that migrate to the site of injury.

From rats to monkeys and humans.

It is now taken for granted that adult neurogenesis occurs in humans, and the idea has revolutionized the way we think about the brain. It is widely believed that physical and mental exercise can stimulate hippocampal neurogenesis, which reverses age-related cognitive decline and may protect against depression and Alzheimer's disease. "Everyone would like to believe that functional neurogenesis occurs in adult humans," says Lumsden. "Everyone would like to believe that we can fix damaged brains, but there is very little evidence for that."

The biggest skeptic isPasko Rakic, who discovered how newborn cells migrate to the developing brain in a series of classic experiments in the early 1970s: Rakic ​​injected monkey fetuses with radioactive thymidine and sliced ​​their brains into hundreds of ultrathin slices. He identified the migrating neurons from his newly synthesized radioactive DNA and carefully reconstructed the sections to show that the cells ascend into elongated cells called radial glial cells, which traverse the thickness of the tube to touch its inner and outer surfaces and then crawl out. like an amoeba. ., along the radial glial fibers towards the outer surface. His hand-drawn diagrams describing the process appear in textbooks to this day.

Now Chair of the Department of Neurobiology at Yale and Director of theKavli Institute of NeuroscienceCasting a long shadow, Rakic ​​is extremely critical of some research on adult neurogenesis. He claims that BrdU can induce cell division, and alsomark dying cells, which synthesize DNA near death, cannot therefore provide accurate counts of newborn cells in adult brain tissue. This can be overcome by double staining with other antibodies to confirm that the BrdU-labeled cells are dividing.

Rakic ​​has published evidence for and against adult neurogenesis in monkeys. He estimates that neurons added to the adult human hippocampus take a year to mature and argues that antidepressants cannot work to stimulate neurogenesis because their effects take about a month to become effective.

“Rakic ​​reasonably requested higher levels of evidence,” says Nottebohm, “but he attacked adult neurogenesis so aggressively that it struck many as a defense of ancient dogma.” As a participant in the battles, I found it very negative.” and not particularly insightful. His own work used animals raised in conditions that inhibit the formation and survival of new neurons.”

Nottebohm and others say that Rakic ​​held back neurogenesis research in adults, but according to Gage, he was "one of the main drivers in making the field more rigorous. He challenges the weaknesses of his work and relies on researchers in the field to solve them." However, Gage notes that immature neurons in mouse stem cells are more active than their mature counterparts, so a longer maturation time could actually be beneficial. "I'm not surprised that maturation takes longer in humans, but the other way of looking at it is that newborn cells have a longer period of plasticity."

However, Rakic's skepticism is supported by scientific evidence, or rather the lack of it.

1998 Gage and the late Peter Erikssonexamined the brains of five cancer patientswho had been injected with BrdU for diagnostic purposes. They treated hippocampal tissue with antibodies against BrdU and proteins synthesized by immature neurons and found some staining in the dentate gyrus. This was the first evidence that the adult human brain contained newborn neurons, but the researchers emphasized that it did not prove that the cells were functional.

Others have isolated stem cells from different regions of the adult human brain. These cells have a limited capacity for self-renewal when grown in the laboratory, but they can produce mature astrocytes, oligodendrocytes, and neurons with normal electrical properties.

Em 2006,jonah's friezefrom the Karolinska Institutet and colleagues examined the cortex in the autopsied brains of seven adults. They looked for radioactive carbon from Cold War atomic bomb tests accumulating in newly synthesized DNA, but only detected atmospheric levels and came to the conclusion.Neurogenesis does not occur in the cortex..

More recentlyGerd Kempermannof the Center for Regenerative Therapies in Dresden and colleagues examined the brains of 54 people aged up to 100 years with antibodies against various proteins and foundsmall number of newborn hippocampal cellsIn all. "It appears to be the same as in rodents," says Kempermann. “There is a very sharp decline early in life, but towards the end it remains a very low level. We saw small numbers of cells, but we saw them until very late in life."

butArturo Alvarez-Buylla, a professor in the Department of Neurological Surgery at the University of California, San Francisco, is not entirely convinced. "Gage and Erikkson provided evidence that some proliferation occurs in the adult hippocampus," he says, "but this should be treated with caution, as some of the labeled cells may have died."

Alvarez-Buylla earned her Ph.D. worked with Nottebohm on songbirds before turning to rodents, where he showed that newborn neurons travel long distances to the olfactory bulb. He has since published several studies suggesting that this migration is unlikely to occur in adult humans. Work withNader Sanai, director of the Barrow Brain Tumor Research Center in Phoenix, Arizona, examined the brains of about 100 people of all ages and a similar number of tissue samples collected during neurosurgery.

identifieda 'ribbon' of astrocytesin the walls of the lateral ventricles producing immature neurons, astrocytes and oligodendrocytes and which has not been observed in other species. They also identified the RMS in infants and found that it contains a small number of migratory cells, as well as a previously unidentified migratory pathway that branches off the RMS to invade the prefrontal cortex.

According to their data, migration in both streams occurs after birth, but declines abruptly by 18 months of age and disappears almost completely by early adulthood. "We concluded that if there is migration, it is very little", says Alvarez-Buylla, "and that the cells do not form large bundles that migrate towards the olfactory bulb".a 2007 study by Erikkson and Maurice Curtis, which saw a robust RMS containing large numbers of migrating cells, but were confirmed last year by Chinese researchers who foundlow number of migratory neurons in adult RMS, but in the olfactory bulb itself there are no new cells.

"How much neurogenesis occurs in older people and how much it contributes to local plasticity are still open questions," says Alvarez-Buylla. “There is controversy about how much cell turnover takes place in the hippocampus and how durable stem cells are over a lifetime. If they shrink with age, they don't really regenerate."

In general, the few available studies indicate that the fountain of youth in adults is thinning. There is no evidence of adult neurogenesis in human cortex; The existence of RMS in adults is still controversial, and evidence of hippocampal neurogenesis in this area is very scarce. When the hippocampus produces new cells, are they enough to be significant?

Kempermann finds it this way: "The network requires very few cells that need to be added and is still functionally relevant," he says. Like other adult neurogenesis researchersa small number of cells may be relevant to hippocampus function🇧🇷 But that question remains unanswered, and the possibility that the number of cells produced is not large enough to be functionally significant has serious implications for popular claims, such as that exercise can improve memory, and also for new brain discoveries. who did this. were suggested. accepted so quickly.

"A side effect of having a big, complex brain is that you don't want naive newcomers breaking in," says Lumsden. “How would new neurons be meaningfully integrated into complex neural networks? At the very least, evolution would have provided mechanisms to eliminate these invaders. The lack of neurogenesis after completion of the brain-wiring scheme would be a selective advantage.”

The brain may therefore prefer stability to plasticity. Adult human neurogenesis may be an evolutionary relic and comes at a very high cost, as stem cells in the adult human brain likely contribute to the formation of brain tumors.

There is still hope

"Rakic ​​was almost right," says Nottebohm. "So far, the overwhelming evidence is that most neurons form early in development, even shortly after birth." But even if functional adult neurogenesis does not occur in the human brain, or if the number of cells produced is too small to be significant, there is still hope that neural stem cells may have therapeutic value.

"Rakic ​​missed the plot point," continued Nottebohm. “There is a rich collection of neural stem cells that produce new neurons well into adulthood. This is extremely important. This shows, in principle, that this reservoir can be used for brain repair purposes.”

To that end, researchers are investigating two approaches to developing neural stem cell-based therapies for neurological disorders, although these treatments still have a long way to go. One approach is to trick brain stem cells into creating neurons that travel to sites of injury or disease. The other is to transplant laboratory neurons of certain types directly into the brain. Indeed, neurons derived from human neural stem cells can, and now can, differentiate into fully functional neurons when transplanted into the brain of a mouse fetus.monitored in live animals using MRI.

“We found the first evidence of replaceable neurons,” says Nottebohm, “and I have no doubt that a whole new field will develop around this concept. I'm sure sooner or later this will have a profound impact. This is just the beginning." ." 🇧🇷