Newborn brain cells modulate learning and memory
La Jolla, CA — Boosted by physical and mental exercise, neural stem
cells continue to sprout new neurons throughout life, but the exact
function of these newcomers has been the topic of much debate.
Removing a genetic master switch that maintains neural stem cells in
their proliferative state finally gave researchers at the Salk
Institute for Biological Studies some definitive answers.
Without adult neurogenesis — literally the "birth of neurons" —
genetically engineered mice turned into "slow learners" that had
trouble navigating a water maze and remembering the location of a
submerged platform, the Salk investigators report in the Jan. 30
Advance Online Edition of Nature. The findings suggest that, one day,
researchers might be able to stimulate neurogenesis with orally
active drugs to influence memory function, the researchers say.
"Our study directly establishes that neurogenesis plays an important
role in a defined process, the acquisition and storage of spatial
memory," says Howard Hughes Medical Investigator Ronald M. Evans,
Ph.D., a professor in the Salk Institute's Gene Expression
Laboratory, who, together with his Salk colleague Fred H. Gage,
Ph.D., a professor in the Laboratory of Genetics, directed the study.
"This finding puts us in a new and important position to exploit the
potential of stem cell-based therapies to improve brain function in
neurodegenerative diseases such as Alzheimer's that are accompanied
by a loss of memory," Evans says.
In an earlier collaboration, Evans and Gage had discovered that TLX,
a so-called orphan receptor is crucial for maintaining adult neural
stem cell in an undifferentiated, proliferative state. Orphan
receptors are structurally related to the well-known hormone
receptors that mediate steroid and thyroid signaling. In contrast, a
TLX regulatory molecule has not yet been identified.
Now, the Salk team wanted to learn more about TLX's biology and
function. However, the global deletion of TLX leads to a variety of
developmental problems, so postdoctoral fellow and first author Chun-
Li Zhang, Ph.D., had to devise a strategy that would allow them to
control when to shut off the gene coding for TLX in neural stem cells
kept in Petri dishes as well as in live animals. When he cultured
mouse neural stem cells without the gene encoding TLX, the
proliferation rate of these cells plummeted and the activity of
hundreds of genes changed.
Explains Zhang, "This experiment confirmed that TLX specifically
induces the genetic program necessary for maintaining neural stem
cells in their stem-like state," handing the Salk researchers the
perfect tool to track the contribution of newborn neurons to normal
brain function — a question Gage is particularly interested in.
"In the past, methods to knock out neurogenesis, such as radiation
and mitotic inhibitors that block all cell division have been rather
crude," he says. "So, maybe not surprisingly the literature is
riddled with contradictory results."
Adult neural stem cells continually generate new brain cells or
neurons in two small areas of mammalian brains: the olfactory bulb,
which processes odors, and the central part of the hippocampus, which
is involved in the formation of memories and learning. Some of these
newborn cells die shortly after they are born but many of them become
functionally integrated into the surrounding brain tissue. Whether
they live or die is regulated by the animals' experience.
Combining mouse genetics and gene transfer techniques, Zhang
genetically engineered mice that allowed him to specifically delete
TLX in the brains of adult mice and thus shut down neurogenesis. He
then put the mice through a battery of standard behavioral tests.
The mice passed with flying colors in all but one test: the Morris
water maze, a common behavioral test in which mice have to rely on
visual cues on the surrounding walls to find and remember the
location of a submerged platform hidden in a pool of milky water.
This task draws on many cognitive abilities, including analytical
skills, learning and memory, and the ability to form strategies.
The more challenging Zhang made the test, the more difficult the
altered mice found it to navigate the maze and remember the location
of the platform. "The mice showed both learning and memory deficits,"
he says. "It's not that they didn't learn, they were just slower at
learning the task and didn't retain as much as their normal
counterparts,
"Whatever these new neurons are doing it is not controlling whether
or not these animals learn," explains Gage. "But these new cells are
regulating the efficiency and the strategy that they using to solve
the problem."
###
Research assistant Yuhua Zou, M.Sc., and postdoctoral researcher
Weimin He, Ph.D., both in the Gene Expression laboratory at the Salk
also contributed to the study.
The Salk Institute for Biological Studies in La Jolla, California, is
an independent nonprofit organization dedicated to fundamental
discoveries in the life sciences, the improvement of human health and
the training of future generations of researchers. Jonas Salk, M.D.,
whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of
land from the City of San Diego and the financial support of the
March of Dimes.
Public release date: 30-Jan-2008
Contact: Gina Kirchweger
kirchweger@salk.
858-453-4100 x1340
Salk Institute
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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