Carnegie Mellon Neuroscientist Receives $1 Million To Understand Neural Integration from the International Human Frontier Science Program-Mellon College of Science - Carnegie Mellon University

Tuesday, July 5, 2005

Carnegie Mellon Neuroscientist Receives $1 Million To Understand Neural Integration from the International Human Frontier Science Program

PITTSBURGH—Carnegie Mellon University scientist Nathan Urban and two international collaborators have received $1 million from the Human Frontier Science Program (HFSP) to work on resolving how a particular "cluster" of neurons contributes to odor perception in the mouse brain. Their proposed research will be the first ever to manipulate brain systems at this intermediate level, a single neuronal module.

By manipulating the tightly coordinated group of neurons that make up a module, the researchers also expect to analyze — for the first time — how the neurons' properties are affected at the cellular level and how their integrated activity affects a mouse's behavior. This research, which links cells to modules to behavior, is key to developing a holistic model of the role specific genes and cells play in an animal's response to an odor.

"Connecting the dots from cell activity to animal behavior will have a profound impact on our ability to understand the brain and to diagnose and treat neural diseases in humans," said Urban. "In many cases we have clues from genetic analyses about the molecular changes that are associated with disorders, but we have little understanding of how these genetic changes impact overall brain function. Focusing on systems at an intermediate level—like the brain modules in the cortex and the olfactory bulb—may allow us to connect the molecular and the functional levels more readily."

Once developed, such an approach could be applied more broadly to other brain areas that have the same kind of modular structure as the olfactory system, including those involved in vision and higher thought processes.


The proposed research is the first of its kind, according to Urban, an assistant professor of biological sciences. "The technological tools that make this type of research possible, including viral gene delivery and in vivo recording and imaging of neurons, are rather novel and in some cases unique to our group."

The group members, which include principal investigator Troy Margrie at the University College London and Pavel Osten at the Max-Planck Institute for Medical Research in Germany, are focusing on the mouse's olfactory bulb, the area of the brain responsible for distinguishing odors. The olfactory bulb contains roughly 1,800 glomeruli, clusters of hundreds of neurons that carry out a particular function. Glomeruli receive sensory input from the nose and relay signals to other areas of the brain. This networking is essential given that a mouse can recognize and process tens of thousands of odors, many of which are critical to its survival, including the scent of food and prey.

With their combined expertise and an innovative research approach, Urban and his collaborators will link the function of a single glomerulus to odor processing at the behavioral level, a task that has been impossible to do until now. Previous studies have investigated the molecular basis of brain function and described neuronal networks by genetically manipulating neurons and studying the outcome. But the techniques used in these efforts affect broad groups of neurons and are unable to target a specific population of cells. For instance, "knocking out" a gene of interest in mice affects areas of the brain outside of the olfactory bulb. Such unspecific genetic manipulation complicates understanding the role a single glomerulus, for example, plays in an animal's behavior.

In a first, Urban and collaborators will genetically modify only neurons in a specific glomerulus that is activated by a known odor. Osten has constructed a gene carrier, or viral vector, to deliver genes that interfere with the cells' electrical activity. The modified cells also will be labeled with fluorescent proteins. Urban, an expert on the functional circuitry of glomeruli in the olfactory bulb, will study how the modified neurons' electrical signals and functions have been affected after treatment with these genes.

In another first, the team will conduct in vivo (live) whole-cell recordings of the modified and labeled cells. Using this technique, which was pioneered by Margrie, they will be able to determine the consequences of genetic manipulations on odor processing in a living animal. Because they can record the electrical activity of neurons in an intact brain, investigators can study the cells' properties in their natural environment. Currently available techniques would require them to sacrifice animals and perform analyses that use artificial stimuli and that remove the neurons from the natural web of connections they form with one another.

Following these studies, the team will expose another group of mice that have undergone this highly localized genetic modification to a target odor and investigate their behavior. The combination of innovative approaches and novel techniques will allow the scientists to link the defined changes in cellular function to odor processing at the behavioral level.

The HFSP awards research grants to teams of scientists from different countries that wish to combine their expertise to address questions that could not be answered by individual laboratories.

The Mellon College of Science at Carnegie Mellon University maintains innovative research and educational programs in biological sciences, chemistry, physics, mathematics and several interdisciplinary areas. For more information, visitwww.cmu.edu/mcs.

For more information, please contact Amy Pavlak at 412-268-8619 orapavlak@andrew.cmu.edu.

 

By: Amy Pavlak