Pinpoint Gene Control Holds Promise For Nervous System Studies

December 24, 1996

Scientists have taken their control over genes one step further by developing a technology to turn on or off a gene in the adult nervous system whenever and wherever they want. Scientists at the University of Rochester report in the January issue of Nature Biotechnology on the first demonstration of the technology: permanently turning on in adult mice the gene for nerve growth factor (NGF), a substance that has been difficult for scientists to study because it's so difficult to manipulate.

Investigators believe the method will make possible important studies into the way our nervous system works. "This technology gives us an unprecedented opportunity to study the function of nearly any gene in the nervous system," says principal investigator Howard Federoff, M.D./Ph.D., chief of the University of Rochester's Division of Molecular Medicine and Gene Therapy.

"The most ideal way to study a gene is to have the ability to turn on or off that gene at any time that you wish, at any place that you wish. This new approach allows us this level of control."

Graduate student Andrew Brooks is first author of the paper. Also contributing were scientist Nariman Panahian, research associate Bhaskar Muhkerjee, and Professor Deborah Cory-Slechta, Ph.D. Brooks presented the work, which is funded by the National Science Foundation, at last month's Society for Neuroscience meeting in Washington.

The Rochester team used a new type of genetic surgery to carry out the experiment. First they created a special strain of mice by inserting extra NGF genes into their DNA, along with a "stop" DNA sequence that kept the genes turned off. Then, when the mice were several months old, scientists injected a viral vector that shuttled into the cells an enzyme that snipped out the "stop" sequence, activating the extra genes to produce NGF. The team believes this is the first permanent genetic modification in the central nervous system of an adult mammal.

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.

The ability to turn on and off genes in the nervous system should help scientists better understand the role of NGF and other neurotrophic factors, substances that help keep our neurons alive and healthy. Scientists believe the presence of such factors helps determine how our brains are wired. For example, like trees shooting out their roots in search of water, neurons in one part of the brain, the basal forebrain, send their projections in search of NGF to the hippocampus. The team plans to study the effect of increased NGF in the hippocampus on these neurons. One area of special interest is the effect of NGF on memory and learning, a link that may be relevant to patients with Alzheimer's disease, where NGF-sensitive neurons in the brain's basal forebrain are among those damaged.
-end-


University of Rochester

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.