Scientists Identify Molecular 'Planner' That Helps Brain Reorganize

Technology Implemented to Create a Smarter Mouse

December 27, 2000

Scientists have used a molecule to help re-wire the brain as an animal is forced to learn from new experiences, much like a highway planner alters a complicated road system working its way through a congested, bustling neighborhood. The study, published recently in the Proceedings of the National Academy of Science, marks the first time scientists have been able to pinpoint a specific molecule that assists the brain to reorganize in the face of new experiences.

In the study funded by the National Institute of Mental Health, neuroscientists at the University of Rochester Medical Center found that genetically engineered mice that were challenged with new tasks enhanced their abilities to learn. Then, in results published in Human Gene Therapy, the Rochester team was able to make a line of mice smarter by boosting the amount of the molecule, nerve growth factor (NGF), in their brains. These mice learned to run unfamiliar mazes more quickly than their unmodified counterparts.

"These studies demonstrate that giving the brain a workout definitely has an impact on brain structure at the molecular level," says first author Andrew Brooks, Ph.D., research assistant professor of neurology in the Center on Aging and Development. "Using your brain is a good thing. Maybe someday we'll know enough about how the brain stores and retrieves information to be able to help prevent people from losing their cognitive abilities prematurely, as we see in some neurodegenerative diseases." Even now, in a study just beginning at the University of California at San Diego, physicians are attempting to do just that, transplanting into the brains of patients with Alzheimer's disease cells that produce NGF.

The circuitry of the brain is a dizzying tangle of nerves connecting billions of different points. It's a little bit like an extensive interstate highway system all squeezed into a few inches of space, with information packets flowing like cars thousands of times each second. Just how that extensive system is established has long been a mystery. The Rochester scientists identified a novel way to direct the "traffic" in an adult animal, finding that NGF plays a role in the wiring and re-wiring of the brain's established highways.

Scientists long held that we're born with all the brain cells, or neurons, that we'll ever have, and that those neurons organize themselves into a hard-wired structure where every neuron has a specific pre-determined role. But in recent years, neuroscientists have discovered that brain cells are incredibly dynamic. They use the term "plasticity" to describe the idea that the brain is flexible, able to handle different tasks and adapt to new circumstances. Brain function is not just a matter of the number and health of neurons, but also how they're organized and how they connect and communicate with each other.

"How is it that the same structure that you are born with allows you to learn to read, to play music, to learn all manner of new tasks?" asks Howard Federoff, M.D., Ph.D., director of the Center on Aging and Development and the principal investigator of the study. "The answer is that the brain is an incredibly dynamic environment, where changes in the wiring allow us to learn new things."

Scientists have had a difficult time pinning down exactly how our experiences affect our brain structure. Using a unique gene-transfer technology developed by Federoff, mice were modified so that cells in the hippocampus, a part of the brain vital to memory and learning, would carry extra copies of a gene that makes NGF. These mice grew up and developed like normal mice. Then, when they reached adulthood after about three months, the NGF gene was turned on, boosting the amount of NGF in those cells within the hippocampus.

Then the scientists ran those mice and their normal counterparts through an experimental set-up designed with collaborator Deborah Cory-Slechta, dean of research and professor and chair of environmental medicine. Mice were divided into three groups: Some spent their days simply milling about, others completed simple rote tasks like running through the same maze day after day, and the third group was continually challenged with a new learning task-navigating a new maze. Researchers found that the combination of increased NGF and a challenging learning environment led to the development of new neuronal connections in an area of the brain vital for memory and learning. The NGF-producing mice that were challenged the most became the quickest, most adept learners. The changes lasted for at least as long as the experiment continued, about eight months - well into middle age for a mouse.

The changes took place in an area known as the basal forebrain; the bundle of nerves connecting this area and the hippocampus are vital for learning and memory. The two areas work in sync, with neurons from the forebrain stimulated by molecules such as NGF that are made in the hippocampus. "It's a little like a phone call, where a cell in the basal forebrain contacts a cell in the hippocampus, and that cell sends a message back to the first. If the first cell likes what it hears, more connections are established," says Federoff.

Federoff and Brooks found that in genetically modified mice who were challenged, neurons in the basal forebrain were on average 60 percent bigger than those in mice that milled about. The modified mice also had more than three times as many neurons connecting to the hippocampus, turning the equivalent of a "two-lane road" connecting these two areas into a much larger "highway." The scientists believe that those added connections boost the learning potential of an animal.

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