March 17, 1998 =

New York Times Science Section

Studies Find Brain Grows New Cells

By GINA KOLATA

For years, neurobiologists clung to a =

fundamental truth: once animals, or people,
reach adulthood, they may lose brain cells
but they can never grow new ones. There were
a couple of exceptions -- in birds and
rats -- but the thought was that these were
peculiarities of nature and not evidence of
a general principle.

But now, in experiments that experts call
amazing, that dogma has been overturned.
Scientists have found that monkeys are
constantly making new brain cells in the
hippocampus, an area of the brain used for
forming long-term memories. Moreover, they
report, the production of new cells is
squelched when the animals are under
extreme stress.

Experts say they fully expect that humans
are no different and that they, too,
make new brain cells in adult life. That
raises the glimmer of a possibility of
eventually treating degenerative disorders
like Alzheimer's or Parkinson's disease and
injuries, like those resulting from stroke
or trauma, by prompting the brain to grow
replacement cells, researchers said.

It also means that neurobiologists must
re-think their notions of how the brain
changes with learning or life experiences.
The new study was by Dr. Elizabeth Gould of
Princeton University, Dr. Bruce S. McEwen
of Rockefeller University in New York and
their colleagues.

"It means that there is a new mechanism
for changing the organization of the adult
brain," said Dr. William Greenough, a
psychologist at the University of Illinois
at Urbana-Champaign who studies learning
and memory in rats.

Dr. Fred Gage, a neurobiologist at the Salk
Institute in San Diego, said the implications
were "fabulously interesting."

The investigators, working with marmoset
monkeys, added two tracer chemicals to the
animals' brains: one that labeled cells
that were dividing, the process that gives
rise to new cells, and one that labeled
mature nerve cells. Cells that were born
during adult life and that grew into mature
brain cells would be marked by both chemicals.

With this method, the researchers looked
for, and found, new cells in the animals'
hippocampuses. Gould estimated that thousands
of such cells were being made each day.
She said she suspected other cells were
dying to make room for new ones, but her
study did not count numbers of dying cells.

The hippocampus was particularly intriguing
for another reason, Gould said. Earlier
research had shown that when people are
under stress, the hippocampus shrinks in
size. For example, people with tumors that
pour out the stress hormone cortisol have a
diminished hippocampus. So do people with
recurrent depression and people with
postraumatic stress disorder, Gould said.
It might be possible, she reasoned, that
monkeys under stress might decrease their
production of new brain cells in the
hippocampus, making that area of the
brain shrink.

To test the hypothesis, Gould and her
colleagues stressed monkeys by putting
a male monkey who had always lived alone
into a small cage where another male was
living. The intruder was terrified and
cowered in the cage, with a rapidly beating
heart. When Gould and her colleagues examined
the brains of the frightened monkeys, they
found that after just one hour of this stress,
the monkeys were making substantially fewer new
brain cells. The study is being published today
in The Proceedings of the National Academy of
Sciences.

As so often happens in science, the seeds
for the new view of brain regeneration were
sown decades ago, but were largely ignored.
In the 1960s, Dr. Joseph Altman, a Purdue
University scientist who is now retired,
reported that rats make new brain cells
throughout their lives. The cells were
in the hippocampus and in the olefactory
bulb, an area used to sense smells, he noted.

"No one paid attention," Gould said.
She attributed the reaction to researchers'
biases. "People thought that there was no
way that such a mechanism could exist in
adult mammals," Gould explained.

Twenty years later, Dr. Fernando Nottebohm,
who is head of the laboratory of animal
behavior at Rockefeller University, asked
whether brain cells were being born in
adult birds. Bird brains, he noticed,
grow and shrink with the seasons, swelling
when the animals need to learn new songs to
attract mates and shrinking after they had
bred. He wondered whether the swelling brains
during breeding seasons could represent the
actual growth of new brain cells. At the time,
Nottebohm said, he knew nothing of Altman's
work. Altman, he said, "was not being quoted
in books."

In a series of painstaking experiments,
Nottebohm showed that birds constantly =

make new brain cells and that the new
cells replace old ones that die. "There
was a program of constant brain rejuvenation,"
Nottebohm said. "Parts of the brain were no
different from the liver or skin. Old cells
died and new ones took their place."

In 1984, Nottebohm organized a meeting in
New York that he called Hope for a New
Neurology. A colleague at Rockefeller,
Dr. Arturo Alvarez-Buylla, recalled that
Nottebohm "was pushing the idea that in
the adult brain, there is no impediment
to the formation of new neurons." But,
Alvarez-Buylla added, "people thought that was
bordering on fantasy."

Nonetheless, some researchers persisted,
showing in rats and mice and in tree shrews
that new brain cells are born throughout life,
at least in the hippocampus and olefactory bulb.
Dr. Alvarez-Buylla, for example, recently found
that adult mice make 5,000 to 10,000 new brain
cells each hour. The brain cells that end up in
the olefactory bulb are born on the walls of the
ventricles, cavities in the brain that are
filled with cerebrospinal fluid. They travel
in "little trains of cells" to their destination,
he said. Those that end up in the hippocampus
are born there.

But many scientists believed that monkeys
and humans could not be growing new brain
cells, and certainly not in a area like the
hippocampus. "People believed that in order
to store memories for a lifetime, you need a
stable brain," Gould said. "If cells are
constantly dying and new ones being produced,
how would that be possible?"

Gould, however, was persuaded by the findings
in other species. "Why not monkeys?" she asked.
Others also began seeking and finding brain
regeneration in monkeys, Gage said, although
Gould is the first to publish her findings.

The results are "very very provocative" said
Dr. Ronald McKay, the chief of the laboratory
of molecular biology at the National Institute
of Neurological Disorders and Stroke in Bethesda,
Md. They lead, he said, to a host of other
questions. How does the rate of nerve cell
regeneration change as monkeys, or people,
grow old? What controls the rate? How can it
respond so rapidly to stress?

Nottebohm has another list of questions.
One of the first imperatives is to understand
why the bulk of new cells seem to be in the
hippocampus. Memories are stored there for
weeks or months and then, it seems, moved
elsewhere in the brain where they reside
permanently. So, Nottebohm said, it is
possible that the hippocampus has "a space
storage crunch" that would cause it to run
out of room for memories if it did not kill
off some cells and replace them with new ones.

The findings also raise the question of
whether new brain cells grow elsewhere in
the brain and, if so, how to stimulate their
growth when the brain is injured or needs
repairs. Scientists have argued that evidence
from stroke or trauma victims and people with
degenerative disorders like Alzheimer's disease
indicates that once brain cells are lost they =

cannot be replaced. But, Nottebohm said, the =

problem might be that scar tissue is interfering
with the reconnection of circuits in the brain,
not that new cells cannot grow. "We know that
when scar tissue is left behind, it interferes
with the reconstitution of circuits" in the brain,
he said.

Gould said Alzheimer patients retain the
immature cells that grow into new hippocampus
cells but lose the nerves that those cells would
connect to. The result is severe memory impairment.

The new work, Nottebohm said, "suggests that
repair is a possibility." And even though new
brain cells have been found, so far, only in
the hippocampus, "it emboldens you to ask,
Why not elsewhere?" he said.

"It is amazing," Nottebohm said.

Copyright 1998 The New York Times Company