Maze and a Molecule Seem to Help Mice Learn

In a laboratory study that could help in deciphering Alzheimer’s disease, scientists found that genetically engineered mice learned and remembered better if subjected to tricky maze exercises.

The research, in which mice were boosted with a neuron-nourishing protein called nerve growth factor, marks the first time a specific molecule has been pinpointed to assist the brain in rewiring itself to tackle new challenges, the University of Rochester said.

“The genetically engineered mice not only learned better than the non-engineered ones but their memory improved,” said lead researcher Dr. Howard Federoff, director of the university’s Center for Aging and Developmental Biology.

“The interaction between the learning experience and this gene caused a rather striking reorganization” in a brain pathway considered vital to spatial learning and memory, he said.

Alzheimer’s is a progressive neurological disease with no known cause or cure that affects more than 4 million Americans. Victims, most of them elderly, suffer gradual memory loss, disorientation and personality changes.

Federoff developed a gene-transfer method used in the study in which extra copies of a gene that generates nerve growth factor are delivered to cells in the hippocampus, a part of the brain thought to be a crucial way station in funneling and retrieving information.

When the mice reached adulthood after three months, a virus was used to turn on the gene. The nerve growth factor allows cells to grow and maintain fibers that link neurons in the brain, even those in distant locations.

The mice and an equal number that didn’t have the gene triggered--about 80 in all--were divided into three groups. Over two weeks, some were kept in their cages, others ran through the same simple maze day after day and a third set was continually challenged to navigate new mazes.

The university study, published in November in Proceedings of the National Academy of Sciences, determined that genetically modified mice were the quickest and most adept learners. Specific neurons in the basal forebrain at the base of their skulls were on average 60% bigger than those in mice not given a workout.

The maze exercises appeared to be a key stimulant “in enhancing the nerve growth factor’s effect on the brain circuitry, in driving the reorganization,” Federoff said.

During nine months of research, long enough for the mice to grow well into middle age, no adverse consequences of the genetic modification were uncovered, he said.

The researchers’ aim was to manipulate a critical pathway in learning that runs from the basal forebrain area to the hippocampus.

“In virtually every single patient who has Alzheimer’s disease, cells that manufacture the neurotransmitter acetylcholine are diseased and their function is profoundly decreased,” Federoff said. “The most modern drugs to treat Alzheimer’s disease are intended to increase the amount of acetylcholine.”

His research team is carrying out further studies to try to develop a strategy in which “we can envision a potential for ameliorating symptoms of Alzheimer’s disease.”

Federoff said he hopes within a few years to conduct clinical trials. Any such project would have to get past extensive regulatory hurdles.

Dr. Bill Thies, vice president for medical and scientific affairs at the Chicago-based Alzheimer’s Assn., said the study holds the promise of developing gene therapies for a variety of neuro-degenerative diseases.

“If something like this works for Alzheimer’s disease, by putting your gene modification in another place you might get it to work for Parkinson’s disease and other diseases where you have a death of nerve cells for a variety of reasons,” Thies said.

Researchers at UC San Diego recently began transplanting cells that produce nerve growth factor into the brains of Alzheimer’s patients. The cells are taken from the patients’ skin and genetically engineered to make more nerve growth factor.

“We would be proposing to modify the existing brain circuitry as opposed to introducing new cells into the brain,” Federoff said. “The jury’s still out, but I firmly believe that approach makes more sense.”

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University of Rochester:

https://www2.envmed.rochester.edu