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Newborn Neurons Search for Meaning

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Science  03 Jan 2003:
Vol. 299, Issue 5603, pp. 32-34
DOI: 10.1126/science.299.5603.32

Some brain regions are replenished with new cells throughout life, but researchers aren't sure what the newcomers contribute to the behaviors those brain regions control, which include singing, smelling, and learning

A neuron is a precious thing. Indeed, until recently, brain neurons were thought to be irreplaceable. Adult brains, we were taught, are unable to make new neurons, so those with which we are endowed at birth must last a lifetime. Major cracks in that dogma began to appear in the 1980s with the discovery that some songbirds—warm-blooded vertebrates like ourselves—give birth to waves of new brain neurons seasonally. Then researchers observed the birth of new neurons—a process called neurogenesis—in the brains of adult mammals, and the old view came crashing down.

Interest in newborn neurons surged, and researchers quickly discovered conditions that turn the birthrate of new neurons up or down. Stress and depression, for example, suppress neurogenesis, whereas exercise, stimulating environments, and antidepressant drugs all give it a boost. A paper in this issue adds pregnancy to the list of neurogenesis-enhancing conditions. But a key piece of the puzzle remains missing, says Larry Squire, a neuroscientist at the University of California (UC), San Diego: “We really don't know anything at all yet about what the function of these new neurons might be.”

That fact can get lost in the hubbub surrounding the field. The notion of pools of new neurons repopulating brain areas is “so seductive,” says Sarah Bottjer, a neuroscientist at the University of Southern California in Los Angeles, “that people get sucked in and lose their perspective.” To many observers, it seems that boosting neurogenesis simply must increase brain power, and that idea has been translated into notions that exercise, stimulating environments, or even sex will improve one's memory or ability to learn. “A lot of what is being said is more speculation than fact,” cautions Tracey Shors, a neuroscientist at Rutgers University in Piscataway, New Jersey. “It is too simplistic to think that if you have more cells you are going to be smarter.”

The dogma dissolves

The first challenge to the “no new neurons” dogma came in 1965. After treating rodents with markers for dividing cells, Joseph Altman and Gopal Das of the Massachusetts Institute of Technology saw cells that appeared to be newly born neurons. But the techniques available at the time couldn't rule out that the cells were glia, support cells in the brain that are known to be replenished, and the results were largely disregarded.

Nearly 20 years later, Fernando Nottebohm and then-graduate student Steven Goldman at Rockefeller University in New York City found evidence of newborn neurons in canaries' high vocal center (HVC), a brain area that helps produce their song. Postdoc John Paton found that the young neurons integrate into the circuitry of the HVC and fire in response to sound. “That gave credibility to the idea that in warm-blooded vertebrates, you could have ongoing neurogenesis in the adult brain,” says Eliot Brenowitz, a neuroscientist at the University of Washington, Seattle. Neurons were continually added to the HVC, but the bulk appeared during times when male canaries learn new song elements. That led Nottebohm to propose that the new neurons were important for song learning.

Neurons that sing.

Like other songbirds, the eastern towhee grows new neurons in song nuclei such as the HVC each breeding season (bottom).

CREDITS: (TOP TO BOTTOM) ADAM JONES/PHOTO RESEARCHERS INC.;ADAPTED FROM ELIOT A. BRENOWITZ, JOURNAL OF NEUROSCIENCE METHODS 121, 75–80 (2002)

Nottebohm's team then discovered neurogenesis in the hippocampus, a brain area critical for spatial learning, in black-capped chickadees. These birds hide seeds in the fall to retrieve later. Postdoc Anat Barnea trapped adult birds, injected them with a label for newborn cells, banded their legs, and released them. She recaptured the birds 6 weeks later and looked for new neurons in the hippocampus. She found new neurons throughout the year, but their numbers peaked when the birds were storing seeds, suggesting that neurogenesis might aid the birds' memory during that critical time.

Once it was established that neurons were born in the brains of adult birds, some researchers argued that birds were a special case. Their need to be light and energy-efficient might have driven them to evolve a system to lose neurons when they don't need them and regrow them when they do.

Then researchers found neurogenesis in the brains of adult mammals. In 1992, Sam Weiss and Brent Reynolds of the University of Calgary in Alberta, Canada, isolated neural stem cells—which can differentiate into neurons—from the subventricular zone of mouse brains. And in 1994, Arturo Alvarez-Buylla and Carlos Lois, then at Rockefeller University, showed that in adult brains these cells form neurons that travel to the olfactory bulb, the brain area that receives sensory information from the nose. Alvarez-Buylla's group, now at UC San Francisco, went on to learn that the new neurons connect to the established circuitry in the olfactory bulb, and Jonas Frisén's team at the Karolinska Institute in Sweden found that they are activated when the bulb responds to smells.

Meanwhile, Fred Gage and his colleagues at the Salk Institute in La Jolla, California, showed that the mammalian hippocampus—as in birds, an important site for memory—also sprouts new cells. His team found neural stem cells in the adult rat hippocampus and subsequently showed that new neurons are born in the hippocampus of adult mice and humans.

Despite all this progress, and some encouraging clues and circumstantial evidence about the role of neurogenesis, researchers studying both birds and mammals are still working furiously to answer the same question: What do these new neurons do?

Neurogenesis on the wing

“The avian system is a little further along” toward an answer, says Alvarez-Buylla, because researchers can work with a well-characterized behavior that varies between species. Male canaries sing elaborate songs during the breeding season and learn new song elements every year. During the nonbreeding season they sing less, their song gets less precise, and their HVC shrinks in size. But when the time comes to embellish their songs again, the HVC enlarges through the addition of new neurons. Zebra finches, on the other hand, learn one song during adolescence and never change it. They also differ from canaries in that they sing and court mates throughout the year. Their brains reflect this difference: Zebra finches add large numbers of neurons to their HVCs only when they are young.

The correlations between neurogenesis and song learning inspired Washington's Brenowitz and then-grad student Tony Tramontin to test another species. Like canaries, song sparrows' singing virtuosity peaks seasonally. But song sparrows are like zebra finches in that they sing the same song throughout life. If neurogenesis in the adult HVC were specifically involved in learning rather than performing a song, Brenowitz and Tramontin reasoned, then song sparrows, like zebra finches, would not add new neurons each season.

Bouncing baby brain cells.

Adult rat brains spawn new cells (red) in the hippocampus.

CREDIT: ELIZABETH GOULD/PRINCETON UNIVERSITY

Tramontin trapped wild song sparrows, injected them with a marker for new neurons, recaptured them, and found, surprisingly, that the sparrows added lots of new neurons to their HVCs seasonally, as canaries do. The results “argue against the hypothesis that the changes evolved specifically to enable these kinds of seasonal changes in learning,” says Brenowitz, but they don't rule out the possibility that, in seasonal song-learners like canaries, the new neurons aid learning.

Another twist came in 2000 when Nottebohm postdoc Constance Scharff, along with Harvard neuroscientist Jeffrey Macklis and other colleagues, simulated in zebra finches the loss and rebirth of neurons that occurs seasonally in canaries. The team selectively killed neurons in the HVC of zebra finches and found that new neurons migrated into the HVC, apparently replacing those that had died. The birds' song was “markedly degraded” after the loss of the neurons, Nottebohm says, but some of the birds' songs returned just as new neurons were added to the HVC. The songs were restored to different degrees but, true to their species, the birds did not sing anything new. Together with Brenowitz and Tramontin's work, that suggests that neurogenesis in the HVC is vital to the birds' ability to sing, but there remains, says Nottebohm, “no direct … evidence that the new neurons are involved with learning.”

Sniffing for a function

As in the bird's song system, researchers have a good idea where new neurons fit into the circuitry of the rat's olfactory bulb, but they are just beginning to get clues about what function the neurogenesis may serve. The new neurons join the ranks of so-called granule cells, which are activated by the neurons that respond to odors. Their primary role is to blunt the activity of neighboring cells.

This blunting helps sharpen the pattern of neural activity evoked by an odor, according to behavioral research done by Pierre-Marie Lledo, Gilles Gheusi, and their colleagues at the Pasteur Institute in Paris. They reported in 2000 that a strain of mutant mice with deficient olfactory neurogenesis, and therefore relatively few granule cells, had difficulty discriminating between paprika and cinnamon, a distinction normal mice can make easily. The mutant mice seemed able to detect and remember odors normally, Lledo says, suggesting that they didn't have an overall deficit in their sense of smell. The study did not distinguish the value of newborn granule cells from those that might have been there all along, however, an issue that the Lledo team is now addressing.

The sense of smell is essential for behaviors more fundamental than distinguishing cinnamon from paprika, including a mother rodent's ability to recognize and nurture her young. That led Calgary's Weiss to wonder if rodent mothers would benefit from an extra influx of new neurons into the olfactory bulb to hone their olfactory discrimination. If so, he proposed, pregnancy might boost olfactory neurogenesis.

A team from Weiss's lab led by postdoc Tetsuro Shingo, working with the lab of their Calgary colleague Jay Cross, injected pregnant rats with a chemical to label new neurons. Neurogenesis rates jumped during pregnancy by 65%, they report on page 117, peaking around the seventh day of a 21-day gestation and again after delivery. They also saw a subsequent increase in new neurons integrated into the olfactory bulb.

The team identified prolactin, a hormone that increases during pregnancy, as the neurogenesis trigger and discovered that mice deficient in prolactin receptors have only half the surge in neurogenesis during pregnancy. Weiss notes that other groups have shown that the receptor-deficient mice tend to ignore their young, a behavior that could be due to an olfactory deficit. But, he cautions, “you have to take that with a big grain of salt, because transgenic animals may display unusual behaviors.”

Pregnancy isn't the only condition that increases prolactin production, Weiss adds: “In males and females one hormone is increased immediately after sexual activity, and that is prolactin.” That fact, coupled with his new report, has led some people to joke that sex must be good for the brain. That's “going off the deep end,” Weiss laughs. “We don't know the relevance that has to human neurogenesis at all.”

Memory's neurons

Such titillating observations aside, most people are less concerned about their olfactory system than they are about the other mammalian brain area where neurons are known to be born: the dentate gyrus of the hippocampus. The hippocampus, which shrinks with age, disease, and depression, is an area that every aging human has an interest in preserving and rejuvenating if possible.

So when the Salk's Gage and his colleagues found neurogenesis in the hippocampus of adult rats, and subsequently showed that housing rats in an enriched environment filled with challenging toys more than doubled the survival rate of new hippocampal neurons and tripled it in aged rats, they generated a lot of excitement. Decades earlier, researchers at UC Berkeley and the University of Illinois, Urbana-Champaign, had shown that exposing animals to enriched environments could increase their mental power and brain size; the new work suggested that at least part of that result might be due to new neurons.

Further correlations between neurogenesis and behavior kept rolling in. In 1999, Rutgers's Shors, with Elizabeth Gould of Princeton University and their colleagues, reported that a challenging learning task, in which rats learned to associate a sound with a later shock to the eyelid, enhanced the survival of newborn neurons in the dentate gyrus. Gage and postdocs Henriette van Praag and Gerd Kempermann found that running in an exercise wheel increased rats' dentate neurogenesis by a whopping 80%. Meanwhile, other groups, including Bruce McEwen's at Rockefeller University, showed that depression or stress diminish neurogenesis in the dentate, and Ronald Duman and his colleagues at Yale University discovered that antidepressant drugs give neurogenesis a boost.

Living up to expectations.

After 4 weeks, some fresh cells (green) look and act like established neurons.

CREDIT: F. GAGE/SALK INSTITUTE

Out of this work a picture was emerging of three crucial steps in the life of new neurons: birth, differentiation into neurons, and survival. And different manipulations variously affected all three steps.

To better understand what the new neurons might be doing, researchers wanted to see them in action. Most experiments on neurogenesis and neuron survival had used a label that cannot reveal whether new neurons become integrated into the brain's circuitry. To get around this problem, van Praag, Gage, and their colleagues injected mice with a fluorescent marker that could be seen under a microscope while the neurons were still alive. With this method, “you can take brain slices and find when the cells functionally integrate into the circuit,” says Gage. Van Praag reported in February that 1 month after injecting the label, she saw newly born neurons linked up to the hippocampal circuitry and functioning. “The new cells actually [fire],” says Gould. “That really suggests that they are doing something.”

A number of experiments have suggested that the new neurons might boost learning. The evidence has been correlational, however, and it doesn't all agree. The early data “seemed to fit with the idea that more neurons enhanced learning and fewer new neurons would be detrimental to learning,” says Gould. “But now there are also reports that suggest the opposite or have found no correlation between the number of new neurons and learning.” For example, Eberhard Fuchs and his colleagues at the German Primate Center in Göttingen recently reported that stress decreases dentate neurogenesis in adult tree shrews, but the stressed shrews were better at a spatial navigation task than controls. Gage's team found that a maze-learning task did not enhance neurogenesis. And Michela Gallagher of Johns Hopkins University in Baltimore, Maryland, reported at the Society for Neuroscience meeting in Orlando, Florida, in November that although cell proliferation in the dentate declines with age in rats, some aging rats perform as well as young rats on memory tests. “The state of the field now reminds me of when you go to clean your office,” says Gould. “It gets a lot worse before it gets better. We are in that stage where we've pulled everything out of the desk, and it's a big mess.”

Some of the confusion, Gage says, may arise because many studies have simply measured the birth of new cells without verifying that those cells become neurons, a practice that can miss shifts in the percentage of new cells that become neurons. Beyond more rigorous identification of neurons, “what is needed are some good techniques for selectively stopping neurogenesis,” to get to the issue of cause and effect, says UC San Diego's Squire, and everyone in the field seems to agree. Last year, Shors and Gould took a stab at stopping adult neurogenesis. They treated rats with a drug called MAM that blocks neurogenesis by killing dividing cells. They used a dose that didn't make the rats overtly sick but depleted dentate neurogenesis by 75% and found that the treatment diminished the rats' ability to perform the eye-blink test. Other groups have used x-rays to block neurogenesis and have found an impact on learning.

But such treatments might have other unknown effects on the brain. The studies “are really confounded [because] if you see a decrease in performance, it may be due to the fact that the animal is sick, or you have affected some other brain region, or some other process in that same brain region,” says Gould. Much better, researchers agree, would be transgenic animals in which researchers could selectively thwart neurogenesis in particular regions at particular times.

That is something “we dream of doing,” says UC San Francisco's Alvarez-Buylla, and many groups are working hard to make the dream a reality. In anticipation of a model system that can provide clear answers, people in the field are already lining up to place bets on whether adult neurogenesis plays an essential role in learning or other brain functions. “I'm on the optimistic side,” says Gage. “I think it does, and we are going to find out how.”

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