Pinpoint Gene Control Holds Promise For Nervous System Studies

The work gives scientists the ability to study genes in a way they've never been able to before. Many genetic studies are based on mice where a particular gene has been knocked out for life. But this can't be done with genes that are vital for development, such as NGF: Knocking them out in an animal that is still developing usually kills the organism.

"In our system, the animal develops as it normally would," says Brooks. "Then we alter it later and study the molecular and behavioral changes. We can go into any region of the central nervous system, at any time during adulthood, and make a permanent genetic modification."

Such control is especially noteworthy in the brain because of its networking properties, notes Dr. Federoff. "The brain is more than the cellular constituents that comprise it -- its power comes from its networking. If we truly want to understand how the brain works, we must study it with methods that don't damage cellular connections and interactions. This new approach provides a way of making small changes in one part of a network and then following changes elicited elsewhere."

As its first gene subject, the team chose NGF, an essential substance for development but less understood in the adult. Ten to 14 days after the injection of one microliter of solution containing about 200,000 replication-defective herpes amplicon viral vector particles into their brains, mice are more active than their normal counterparts, running around their cages more and rearing up on their hind legs many times as often as their normal counterparts.

The genetic alteration also leads to a greater than 10-fold increase in the amount of NGF in the hippocampus, the region of the brain where scientists inject the virus. The team has detected these elevated levels for as long as they've run their experiments -- one year. Brooks and Dr. Federoff are studying precisely how increased NGF levels are causing these changes in the animals' behavior

Contact: Tom Rickey
University of Rochester

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