Grow your own
New Scientist, 12 February 2000
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.
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
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).
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.
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.
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".
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.
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
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.
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.
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 luxuryGage
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.
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.
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.
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.
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.
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.
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.
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."
1. Further reading: Neurogenesis in adulthood: a possible role in
learning by Elizabeth Gould, Trends in Cognitive Sciences, vol 3, p 186
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).
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.