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Newborn brain cells modulate learning and memory
January 30, 2008
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," observes Zhang.
"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.
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