Young Cells in Old Brains: Scientific American/ Brain Degeneration Reversed

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August 15, 2001 Search www.feat.org/search/news.asp

SCIENCE

* Young Cells in Old Brains: Scientific American

* Brain Degeneration Reversed in Mice

Young Cells in Old Brains: Scientific American

The paradigm-shifting conclusion that adult brains can grow new neurons owes

a lot to Gould's rats and monkeys

[This new knowledge of the brain may play a key role in autism

research and treatment.]

http://www.sciam.com/2001/0901issue/0901profile.html

• Past thinking: Memories are stored by locked-in neural

connections. Present: The brain can add neurons, perhaps to

establish new memories.

• Hope for dementia: New neurons seem able to migrate,

suggesting that therapeutic cells can be guided to areas damaged

by disease or injury.

• Use it or lose it: In lab animals not kept in a

stimulating cognitive environment, " most new neurons

will die within a few weeks. "

Princeton, N.J.--Reunion weekend at Princeton University, and the

shady Gothic campus has been inundated by spring showers and men in boaters

and natty orange seersucker jackets. Tents and small groups of murmuring

alumni dot the courtyards. Everything proper, seemingly in its place. In

Green Hall, however, the same order does not prevail. Gould's

laboratory is undergoing construction, and the neuroscientist herself would

not be mistaken for an alum: her plaid blue workman's shirt hangs loosely

and unbuttoned over a T-shirt and jeans, and she confesses she often feels

out of place on the conservative campus.

Against a backdrop of tidy ideas about the brain, Gould and her

colleagues have been messing things up and, in the process, contributing to

some of the most exciting findings of the past decade. Her work--and that of

several other neuroscientists--has made clear that new neurons are produced

in certain areas of the adult brains of mammals, including primates.

Moreover, these cells can be killed off by stress and unchallenging

environments but thrive in enriched settings where animals are learning, and

they may play a role in memory.

Until recently, dogma held that mature brains were static: no cells

were born, except in the olfactory bulb. One of the cornerstones of this

understanding came from studies by Pasko Rakic of Yale University, who

examined macaque monkeys and found no evidence of the creation of nerve

cells, a process called neurogenesis. The prevailing view has since held

that primates--and, indeed, mammals in general--are born with all the

neurons they are going to have. Such neural stability was considered

necessary for long-term memory. So in the late 1980s when Gould, who was

then researching the effect of hormones on the brain as a postdoctoral

fellow in the laboratory of Bruce S. McEwen at the Rockefeller University,

saw evidence of new neurons in the rat hippocampus, she was perplexed. Gould

knew from the pioneering work of Nottebohm, also at Rockefeller,

that neurogenesis occurred in adult birds--canaries and zebra finches, for

instance, grow nerve cells to learn new songs--but she and her lab mates

knew of no mammalian parallel. " We were really puzzled, " she recalls. " It

wasn't until we delved far enough back into the literature that we found

evidence that new neurons are produced in the hippocampus. "

Those earlier studies had never been widely noticed. Beginning in the

1960s ph Altman, now professor emeritus at Purdue University, and

neurologist S. Kaplan independently recorded neurogenesis in rats

and other mammals. They saw growth in the olfactory bulb, in the

hippocampus--a region important to memory--and, most strikingly, in the

neocortex, which is the part of the brain involved in higher thinking. " But

nobody picked up on the results, " Gould says. " It is a classic example of

something appearing before its time. "

In her work with rats, Gould verified that when she altered the normal

hormonal bath the hippocampus received, cells died and, apparently to

compensate, more cells were born. " That was really the beginning of my

interest in neurogenesis and my realization that it happened, " she says.

" But at that time, to be perfectly honest, I was more interested in solving

the puzzle of my own data and not so much into saying, 'Hey, this is a

really cool phenomenon that has been overlooked and that has a lot of

meaning.' " Her first papers on the phenomenon, published in 1992 and 1993,

did not attract much attention.

Gould went on to do experiments clarifying aspects of neurogenesis.

She found that stress suppressed the creation of neurons and that lesions in

the hippocampus triggered the development of new cells--something she

considers significant because it implies that the brain can heal, or be

induced to heal, after injury.

In 1997 Gould, who grew up in Huntington, N.Y., moved to Princeton as

an assistant professor. Over the next few years she and her co-workers

reported that new neurons survived if animals lived in complex environments

and learned tasks, findings also documented in mice by Fred H. Gage of the

Salk Institute for Biological Studies in La Jolla, Calif. Gould then

observed that new neurons are found not just in the rat hippocampus but also

in those of marmoset monkeys and macaques. News of neurogenesis in primates,

including confirmatory work by Rakic in macaques and by Gage in the human

hippocampus, catalyzed widespread interest because it introduced the

possibility of repairing the brain and elucidating memory formation.

For Gould, the sudden splash of attention has been disorienting--and

she does not relish it, particularly when it takes her away from her

experiments. She says she is happiest in the lab, working under the

microscope with brain slices, which she finds beautiful and which recall a

childhood interest in being an artist. And she has liked being in a quiet

field of research, one she chose when studying psychology at the University

of California at Los Angeles. " I have no interest in doing experiments that

someone else is going to do a month later if I don't get around to it, " she

says. " You have to pick things to do that are really intriguing to you,

things that you are really curious about--not just because you want to

publish on them before anyone else does. "

Her curiosity is taking her in several directions these days. An

outstanding question centers on what role new hippocampal neurons play. Do

they establish new circuits or memories? Or do they replace old neurons in

established circuits? This year Gould and her colleagues reported that the

neurons are involved in the creation of trace memories--memories important

to temporal information. " We had evidence that the new cells were affected

by learning, and this is evidence that the new cells are necessary for

learning, " Gould explains. She now intends to do similar studies in

marmosets, to see whether her discoveries about rats will prove true for

primates.

Gould is also repeating and extending work of a few years ago in which

she found neurogenesis in the neocortex of macaques, a finding that remains

controversial and that would be highly significant because of the importance

of the cortex. Although no one has published a replication so far,

T. Greenough of the University of Illinois says Gould's findings " do not

surprise me. We have unpublished data in rats that support the same thing. "

In addition, Gould has begun investigating the role of sleep

deprivation in neurogenesis, an interest triggered by the birth of her third

child last year. " I never really thought about the sleep aspect until I

wasn't getting any, " she says, laughing. And she is intrigued by the

possibility that much of what we have come to understand from laboratory

settings may be skewed.

" Our laboratory animals are very abnormal, " Gould notes. " They have

unlimited access to food and water, and they have no interesting cognitive

experiences at all. We know that if you house an animal in that setting,

most of its new neurons will die within a few weeks after they are

produced. " Gould is designing environments that are closer to the ones rats

and marmosets experience in the wild, hoping to get closer to the truth

about the brain. " It really raises the issue of whether a lot of the things

we are looking at are really deprivation effects. "

Potentially shifting another paradigm doesn't faze Gould. " There has

to be some fresh perspective, something new that you can bring to the work

that other people wouldn't see, " she says. " Otherwise you are not making a

real contribution, and you might as well just step aside and find something

else to do. "

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Brain Degeneration Reversed in Mice

[by Nicolle Charbonneau HealthScoutNews.]

http://dailynews.yahoo.com/h/hsn/20010814/hl/brain_degeneration_reversed_in_

mice_1.html <-- address ends here.

Brain cells that were presumed to have died in elderly patients with

Down syndrome or Alzheimer's disease (news - web sites) may only have been

cut off from a crucial protein, says new research.

And a direct infusion of the protein appears to restore the cells

completely in mice, suggesting that similar neuro-degeneration in humans

could be reversed, the study says.

Stanford University researchers looked at a group of cells in an area

of the brain called the basal forebrain, which along with the hippocampus is

crucial for learning and memory.

" We know that these are populations of cells that degenerate in both

Alzheimer's disease and Down syndrome, " says lead study author

, a senior lecturer in experimental neuropathology at King's College

in London. The research appears in today's issue of the Proceedings of the

National Academy of Sciences (news - web sites).

The cells, called basal forebrain cholinergic neurons, shrivel up or

die as patients with these disorders age, contributing to their cognitive

decline.

and his colleagues say they believe the degeneration of these

neurons is related to a problem in the transport of nerve growth factor, a

protein critical to brain development and function.

In mice with a condition comparable to Down syndrome in humans,

found that something was interfering with the pathway that nerve growth

factor follows to the basal forebrain.

" They're still making this protein, " but says , " Somehow,

there's some kind of roadblock that prevents it from getting back [to the

basal forebrain]. "

To bypass the roadblock, the researchers directly infused the spaces

around the basal forebrain with nerve growth factor.

" We found two very surprising and exciting things. The remaining cells

that were there that looked shrunken were actually restored to their full

size, and this was even in the old, 18-month-old animal, " says .

" More excitingly still, it completely restored the number of these

cells, " suggesting that cells presumed dead may actually have been in a

dormant state until the nerve growth factor returned, he says.

says the findings raise hopes of reversing neuro-degeneration

in humans with Down syndrome and Alzheimer's, particularly if treatment

could be started at an early stage of neuro-degeneration.

However, the researchers say they can't yet tell whether the nerve

growth factor restores the cells' function and what causes the interference

with the transport of nerve growth factor to the basal forebrain in the

first place.

Dr. Federoff, director of the University of Rochester's Center

for Aging and Developmental Biology in Rochester, N.Y., says the findings

are of considerable interest for research into Down syndrome and Alzheimer's

disease.

" The fact that they can restore that signaling by the infusion of

nerve growth factor suggests to me … this may have some ultimate therapeutic

value, " says Federoff.

Although the researchers were able to reverse the neuro-degeneration

in an older mouse, he says treating the problem as early as possible would

be better. " The longer that you let that process go on, the neuron is going

to be less capable of fully recovering, " says Federoff.

says upcoming studies will look for the functional effects of

the treatment in animals and determine any side effects.

More than 350,000 people in the United States have Down syndrome,

while approximately 4 million Americans have Alzheimer's disease.

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