Grow your own

New Scientist, 12 February 2000
ALISON MOTLUK

FOR so long, it was an article of faith: adults don't grow new brain cells. Unlike your skin, blood and most other parts of the body, where old cells die and are replaced, the adult human brain simply doesn't get refreshed. The neurons you learned to walk with will be the very same ones you'll use to master the Zimmer frame.

Even when researchers discovered that mice, birds and some monkeys routinely produce new brain cells in adulthood, the hardliners still clung to the notion that people were different. To protect all the things we learn and remember, we'd had to sacrifice that ability, they contended (see "Long memories").

But now this orthodoxy has been overturned. In November 1998, Fred Gage of the Salk Institute for Biological Studies in California and his colleagues there and at the Sahlgrenska University Hospital in Sweden published proof that humans are not unique. We too are producing new brain cells well into adulthood ( Nature Medicine, vol 4, p 1313).

Grand purpose

Gage's finding has opened the floodgates. Everything known about neurogenesis—the birth of new neurons—in animals is being looked at again with people in mind. There are all sorts of questions to answer. What happens to these new neurons after they are born? Does neurogenesis have some grand purpose? Is there anything we can do to encourage more to sprout and fewer to die off?

The tidal wave of new research done in the past year and a half suggests that, yes, anything from exercising to mood can influence how many neurons are born each day, and how many survive. It is providing fresh insights into how memories form and take root. And some researchers are even starting to explore the possibility of improving people's recovery from brain injury by exploiting this ability to grow new nerve cells.

The evidence for neurogenesis came when Gage's team looked at the brains of five people who had died of cancer. The doctors treating the cancer patients had injected them with bromodeoxyuridine (BrdU), an analogue of one of the nucleic acids, thymidine, which becomes part of the DNA of new cells. Doctors can use this chemical label to measure how many new cancer cells are being born, by doing a biopsy. But since BrdU tags every new cell, not just cancerous ones, Gage's team realised it should also reveal whether new neurons were being formed. So they arranged to get their hands on some post-mortem brain tissue.

The team found overwhelming evidence for neurogenesis. "All of the patients showed evidence of recent cell division," says Gage, even though they weren't especially young or healthy. The researchers knew the new cells weren't tumour cells, as the patients had been suffering from cancers confined to the mouth and throat. And close scrutiny confirmed that the new cells were definitely neurons.

All the neuron growth that Gage saw was in a region of the brain called the dentate gyrus, which is part of the hippocampus, a region that is involved in learning and memory. Most neuroscientists agree that in many species new neurons form in the olfactory bulb, too, the part of the brain that senses smell. And while Gage found labelled cells in other parts of the brain, he didn't think that they were neurons. But whether neurogenesis happens anywhere else in the brain is still a matter of heated debate. Elizabeth Gould, a neuroscientist at Princeton University, claims to have found evidence of neurogenesis in the brain's outermost shell—the neocortex—of adult macaque monkeys, although it isn't at all clear what this means for humans.

Like Gage, she used BrdU to identify new brain cells in 12 macaques and tracked their progress. Two hours after the tracer was injected, most labelled cells were in a region called the subventricular zone (SVZ), which suggests that this might be where the new cells were born. There were still a few lingering there a week later, but by then most appeared to have moved into the white matter of the brain's frontal and temporal (side) regions.

After two weeks, almost all the labelled cells had ventured out into areas of the neocortex. The migrating cells were lined up in a stream running outwards from where they started, Gould reported (Science, vol 286, p 548). "These results suggest that in the adult macaque brain, new cells originate in the SVZ and migrate through the white matter to certain neocortical regions where they differentiate into mature neurons".

Sticky question

There is some scepticism, however. Some researchers think that Gage and Gould may be mistaking new glial cells—the nervous system's support cells—for new neurons. Gage is satisfied that's not the case with his work. But he's not wholly convinced by the macaque study. Sometimes new cells migrate by sticking to the surface of mature neurons, but aren't neurons themselves. "I'm looking forward to seeing it replicated," he says. But Gould says her group is "very confident" that they are seeing neurons: the cells look like neurons, three markers have identified them as neurons and a glial marker has rejected them as glia. They even extend axons, the thread-like projections that link to other neurons, a hallmark of mature neurons, she says.

Gould was intrigued to find that the new macaque neurons entered a part of the neocortex known as the association cortex. Its job seems to be linking information from other brain regions. By forming new synapses, she says, the cells could form new connections between events, resulting in new learning. This seems to be the case in canaries, she says. They temporarily recruit more new neurons into the song circuitry as they're mastering new tunes.

Gage agrees that the new cells may play a role in memory in the hippocampus. Neurogenesis in the olfactory bulb could simply be a hand-me-up from species that depend on their noses more, but in the hippocampus it is more significant, because that's where new memories form in humans and other species.

One theory is that the hippocampus is where sensory information is collected and bundled up before it is put into long-term storage. And the dentate gyrus, the site of neurogenesis, is the first relay station for sensory information coming into the hippocampus. As such, it gets hit with a lot of glutamate, an excitatory neurotransmitter that damages brain cells, Gage says. "What we may have here is repair and replace." To be able to process memories throughout our lifetimes, parcel them up and send them out for safe keeping, new troops may be continually needed in this region.

Just how many new neurons are produced in a human brain on any given day isn't clear, though. Neuroscientists know that a few thousand pop up every day in an adult rat, but extrapolating up the evolutionary scale isn't easy. The guess is that there are fewer, not more, in people. But both Gould and Gage suspect that the new neurons are special, that they share with embryonic neurons the ability to form synapses extremely quickly, allowing them to form a disproportionately high volume of new connections. How else could so few cells have any effect, Gage asks.

It is also not clear exactly how long these new cells hang around, although the evidence suggests many of them last only a few weeks at best. But just because they are short-lived doesn't mean the new cells aren't important, Gould stresses. Why would the body waste energy creating them for nothing? "They might be very important shortly after they're generated," she says. She agrees that they could play a major role in new memory formation in the hippocampus, before those memories are stored elsewhere for the long term.

One of the reasons why it's hard to say how many neurons form, and how long they last, is that their rates of birth and survival seem far from constant. In 1997, Gage and his colleagues showed that an "enriched environment" increased neurogenesis in mice (Nature, vol 386, p 493). But all sorts of factors contributed to this "enrichment"—learning, socialising and exercising, not to mention more exciting cages. Last year, both Gage and Gould tried to tease these factors apart.

Life of luxury

Gage assigned mice to separate categories. Some got to learn, others got to run and others just luxuriated in spacious, well-equipped homes. His team was particularly interested in the effects of voluntary exercise, partly because of a study that suggested rats and mice that had suffered a stroke recovered better if they exercised a lot. Mice given large cages full of toys or unrestricted access to a running wheel showed an increase in the proliferation of new cells, Gage found. Interestingly, forced swims did not have this effect. Nor did learning. But both running and plush cages doubled the number of new cells ( Nature Neuroscience, vol 2, p 266).

Gould came to slightly different conclusions. She was focusing on another aspect of "enrichment": learning opportunities. Gould had been intrigued by a study of neurogenesis in birds by Fernando Nottebohm of Rockefeller University in New York. He showed that black capped chickadees in the wild grow more new hippocampal neurons than those in captivity. For birds in the wild, there is also a seasonal variation in neuronal survival rates, with more new neurons surviving during times of seed storage and retrieval.

So Gould's group looked at whether learning tasks that activate the hippocampus help new neurons survive. A week after injecting rats with the BrdU tracer, they trained half of them on spatial learning tasks that involved the hippocampus, such as using landmarks to find a platform submerged in murky water. The other rats did tasks that do not engage the hippocampus.

The training took place when the neurons born as the BrdU was injected should have started to die off. Yet learning the hippocampus-dependent tasks increased the number of new cells, the researchers found (Nature Neuroscience, vol 2, p 260). So whereas Gage's work suggests that learning can't influence the neuron birth rate, Gould's findings seemed to underscore that old adage, use 'em or lose 'em.

No one is suggesting that we should train for marathons or study obscure Hungarian poetry to cling on to every last neuron. Indeed, many neuroscientists now think the word "enriched" is misleading—"undeprived" might be more accurate. Our normal activities might be quite enough to keep up a healthy supply of new neurons. Still, there are hints that ordinary life events can affect how many neurons are born and survive. Recent work in rodents suggests that certain brain chemicals can affect neurogenesis, for instance. Barry Jacobs of Princeton University recently reported that serotonin, a neurotransmitter involved in mood, can boost the number of new brain cells being formed—even when the increase in serotonin is the result of taking an antidepressant such as Prozac (New Scientist, 6 November 1999, p 6). Oestrogen is also suspected of increasing neurogenesis, which might be why hormone replacement therapy seems to protect older women against mental decline.

Stress hormones, on the other hand, stunt neuron birth and survival. Ron McKay, a neuroscientist at the National Institutes of Health in Maryland, even blames stress for much the mental decline that occurs as we grow older. Levels of stress hormones, or corticosteroids, are up to three times higher in elderly people than in younger adults, and stress is known to impair memory in people of all ages. So McKay removed rats' adrenal gland, which produces most corticosteroids, and then looked at how many new neurons formed. He found that when stress hormone levels were low, neurons divided much more in the old as well as the young (Nature Neuroscience, vol 2, p 894). "It goes up sixfold or more," he says.

Equally provocative are the findings about what happens in mature brains following injury. For nearly a century, it has been believed that adult brains just can't repair themselves after a stroke or recover from the long-term damage inflicted by diseases such as Alzheimer's. Now a few scientists are even challenging this.

Latent potential

It's true that a brain can't recover completely. But according to Daniel Lowenstein, a neuroscientist at the University of California at San Francisco, the rate of neurogenesis increases after an incident such as an epileptic seizure. After inducing epileptic fits in rats, he found a marked increase in the number of BrdU-labelled cells in the dentate gyrus. Some were fully mature neurons, he says, and they appeared to be contributing to the remodelling of the connections. "There are a lot of reasons to be optimistic about a latent potential in humans," he says.

Frank Sharp, also at the University of California at San Francisco, found something similar happens after a stroke. He told a meeting of the American Heart Association last year that neurogenesis in rats goes up 12-fold after a stroke in the hippocampus. "It is not known whether there are new neurons born in the brains of humans following a stroke," he says. "We certainly think there would be." Although people seldom completely recover from a stroke, he says, their memory often improves a bit, and the birth of new neurons could explain why.

But even if brains can be persuaded to make more neurons, the problem may be getting them where they're needed. As Gage emphasised at the Society for Neuroscience's annual meeting in Miami Beach last October, a cell's surroundings are critical. A cell that goes native in one brain region might just lie dormant and useless in another. This became clear when a post-doc in Gage's lab took a tissue sample from a rodent spinal cord and nourished the cells in a dish with growth factors. While new glial cells continually form in the spinal cord, neurogenesis is never seen. "I've looked at the spinal cord over and over again," Gage says. Yet to everyone's surprise, the cells gave rise to neurons as well as to two kinds of glial cell.

And when more cells from the spinal cord were transplanted into the hippocampus, he told the meeting, they responded to the environment the same way as cells born locally do. But by isolating and propagating the cells, he says, they are somehow given the opportunity to do something they couldn't do before.

The hope, of course, is that neurogenesis could be manipulated to dramatically improve people's recovery after brain damage. That isn't going to be easy, however. Without help, the number of new neurons added in adulthood is paltry compared to the number already there—2 million in the adult rat, for example. Not enough to fix a damaged brain. But seemingly enough to keep an old one working.

Indeed, when he sits back to think about it, says Gage, what's really amazing is that there isn't more neurogenesis. "My grandfather was 96 years old," he muses. "That means he had the same motor cortex neurons for 96 years. And he could still walk around."

Bibliography

   1. Further reading: Neurogenesis in adulthood: a possible role in learning by Elizabeth Gould, Trends in Cognitive Sciences, vol 3, p 186 (1999)

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Long memories

THE idea that higher primates do not grow new brain cells may have been, in retrospect, a cocky claim. Researchers long believed that neurons in all species form during embryonic development. But in the 1960s, Joseph Altman, then a biologist at MIT, discovered that new neurons were sprouting in the brains of adult rats and guinea pigs (Nature, vol 214, p 1098). Over the years, the same was found to be true in cats, then chickadees, tree shrews and even marmoset monkeys. But the higher primates, including humans, were different, most neuroscientists maintained. One of the few people to actually go looking for signs of neurogenesis in the primate brain, Pasko Rakic of Yale University, emerged empty-handed. In an influential paper in 1985 entitled "Limits to Neurogenesis in Primates", Rakic speculated that primates, particularly humans, needed a stable set of neurons to be able to remember things. A primate's brain " . . . may be uniquely specialised in lacking the capacity for neuronal production once it reaches the adult stage," he wrote (Science, vol 227, p 1054).

Rakic's study was compelling. He examined hundreds of brain slices from 12 rhesus monkeys. All the monkeys had been injected with radioactive thymidine to label new cells. He knew the marker worked: it showed up in all renewable tissues, such as the skin and spleen.

But Rakic found absolutely no evidence of neurogenesis in the adult monkeys. "Not a single heavily labelled cell with the morphological characteristics of a neuron was observed in the brain of any adult animal," he reported. Adult primates, he concluded, did not produce new neurons. Complex and expensive, the study was never directly replicated. Nevertheless, Rakic's findings became a cornerstone of belief in how the adult primate brain works: stability comes at the cost of plasticity.