快猫短视频

FOR so long, it was an article of faith: adults don鈥檛 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鈥檛 get refreshed. The
neurons you learned to walk with will be the very same ones you鈥檒l 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鈥檇 had to sacrifice that ability, they contended (see 鈥淟ong memories鈥�).

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鈥檚 finding has opened the floodgates. Everything known about
neurogenesis鈥攖he birth of new neurons鈥攊n 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鈥檚 recovery from brain injury by exploiting
this ability to grow new nerve cells.

The evidence for neurogenesis came when Gage鈥檚 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鈥檚 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. 鈥淎ll of the patients
showed evidence of recent cell division,鈥� says Gage, even though they weren鈥檛
especially young or healthy. The researchers knew the new cells weren鈥檛 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鈥檛 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鈥檚 outermost shell鈥攖he neocortex鈥攐f adult macaque monkeys,
although it isn鈥檛 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鈥檚 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).
鈥淭hese 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鈥�.

Sticky question

There is some scepticism, however. Some researchers think that Gage and Gould
may be mistaking new glial cells鈥攖he nervous system鈥檚 support
cells鈥攆or new neurons. Gage is satisfied that鈥檚 not the case with his
work. But he鈥檚 not wholly convinced by the macaque study. Sometimes new cells
migrate by sticking to the surface of mature neurons, but aren鈥檛 neurons
themselves. 鈥淚鈥檓 looking forward to seeing it replicated,鈥� he says. But Gould
says her group is 鈥渧ery confident鈥� 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鈥檙e 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鈥檚 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. 鈥淲hat we may
have here is repair and replace.鈥� 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鈥檛 clear, though. Neuroscientists know that a few thousand pop up every day
in an adult rat, but extrapolating up the evolutionary scale isn鈥檛 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鈥檛 mean the new cells aren鈥檛 important, Gould
stresses. Why would the body waste energy creating them for nothing? 鈥淭hey might
be very important shortly after they鈥檙e generated,鈥� 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鈥檚 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 鈥渆nriched environment鈥� increased
neurogenesis in mice (Nature, vol 386, p 493). But all sorts of factors
contributed to this 鈥渆nrichment鈥濃�攍earning, 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 鈥渆nrichment鈥�: 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鈥檚 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鈥檚 work suggests that learning can鈥檛 influence the
neuron birth rate, Gould鈥檚 findings seemed to underscore that old adage, use 鈥檈m
or lose 鈥檈m.

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 鈥渆nriched鈥� is misleading鈥斺�漸ndeprived鈥� 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鈥攅ven when the increase in serotonin is the result of taking an
antidepressant such as Prozac
(快猫短视频, 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鈥� 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). 鈥淚t goes up
sixfold or more,鈥� 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鈥檛 repair themselves after a stroke or recover from the long-term damage
inflicted by diseases such as Alzheimer鈥檚. Now a few scientists are even
challenging this.

Latent potential

It鈥檚 true that a brain can鈥檛 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. 鈥淭here are a lot of reasons to be optimistic about a latent
potential in humans,鈥� 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. 鈥淚t is not known whether there are new neurons born
in the brains of humans following a stroke,鈥� he says. 鈥淲e certainly think there
would be.鈥� 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鈥檙e needed. As Gage emphasised at the Society for
Neuroscience鈥檚 annual meeting in Miami Beach last October, a cell鈥檚 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鈥檚 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. 鈥淚鈥檝e looked at the spinal cord over and over
again,鈥� Gage says. Yet to everyone鈥檚 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鈥檛 do
before.

The hope, of course, is that neurogenesis could be manipulated to
dramatically improve people鈥檚 recovery after brain damage. That isn鈥檛 going to
be easy, however. Without help, the number of new neurons added in adulthood is
paltry compared to the number already there鈥�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鈥檚 really amazing
is that there isn鈥檛 more neurogenesis. 鈥淢y grandfather was 96 years old,鈥� he
muses. 鈥淭hat means he had the same motor cortex neurons for 96 years. And he
could still walk around.鈥�

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 鈥淟imits to
Neurogenesis in Primates鈥�, Rakic speculated that primates, particularly humans,
needed a stable set of neurons to be able to remember things. A primate鈥檚 brain
鈥� . . . may be uniquely specialised in lacking the capacity for neuronal
production once it reaches the adult stage,鈥� he wrote (Science, vol 227, p
1054).

Rakic鈥檚 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.
鈥淣ot a single heavily labelled cell with the morphological characteristics of a
neuron was observed in the brain of any adult animal,鈥� he reported. Adult
primates, he concluded, did not produce new neurons. Complex and expensive,
the study was never directly replicated. Nevertheless, Rakic鈥檚 findings became a
cornerstone of belief in how the adult primate brain works: stability comes at
the cost of plasticity.