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Research View is published twice a year by the offices of the Vice President for Research and Development and University Relations at The University of Montana. Send questions, comments or suggestions to Rita Munzenrider, managing editor, 327 Brantly Hall, Missoula, MT 59812, or call (406) 243-4824. Production manager and designer is Cary Shimek. Contributing editors and writers are Patia Stephens, Shimek and Vince Devlin. The photographer is Todd Goodrich. For more information about UM research, call Judy Fredenberg in the Office of the Vice President for Research and Development at (406) 243-6670.
Transverse hippocampal slices. Glutamate transporters. Synaptic plasticity. Endocannabinoids. Long-term potentiation. There are a lot of fancy terms to wrap your brain around when it comes to understanding UM Professor Michael Kavanaugh’s research, so let’s ease ourselves into the water.
What would be a wading pool for children becomes a swimming pool if you put an animal in it whose legs aren’t long enough to reach the bottom.
Say, a mouse.
Add a handful of simple things – a small platform just below the surface of the water that the mouse can’t see. Some symbols on the side of the pool, such as an “X,” an “O” and a star.
Suddenly, the 4-foot-wide pool becomes a portal into the workings of the brain.
Put a mouse into the pool for the first time and it will swim hither and yon searching for an escape, often hugging the sides of the pool hoping that will lead to land. Only by chance might it stumble on the small platform, located midway between the pool’s center and side.
Usually, the mouse never finds it. After 90 seconds in the water, Kavanaugh will rescue the mouse and set it on the platform. From there, the rodent can examine its surroundings. There’s the star. There’s the “X.” There’s the “O.” This is where I am at in the water.
The next day the mouse goes for another dip. And the next and the next and the next until, after seven straight days, Kavanaugh – a neurophysiologist and UM faculty member in the College of Health Professions and Biomedical Sciences – can put the mouse in the pool and watch it swim to the platform in as little as three seconds.
“Normally, every day the mouse gets a little faster,” says Kavanaugh, who can also track the patterns mice choose to swim each day on a computer.
How the mouse learns to locate the platform, and how it remembers it, is part of Kavanaugh’s ongoing research.
“We’re interested in brain function, all the way from single molecules up to behavior,” says Kavanaugh, an investigator with the National Institutes of Health Center for Structural and Functional Neuroscience, which was established at UM as a Center for Biomedical Research Excellence.
Communication of information between neurons is accomplished by movement of chemicals across a small gap called the synapse. Chemicals, called neurotransmitters, are released from one neuron at the presynaptic nerve terminal. Neurotransmitters then cross the synapse where a signal is generated when they bind to the next neuron at a specialized site called a receptor.
Each neurotransmitter has a specific transporter that helps to terminate its signal by taking it back into the neuron, and the transporter that most interests Kavanaugh is the glutamate transporter.
“Glutamate is the most abundant neurotransmitter in the brain,” Kavanaugh says, “and it’s the key in learning and memory.”
By also studying “knockout mice” – mice that have been genetically engineered to remove one of the five glutamate transporter genes – Kavanaugh and his graduate students can gain even more insight into the normal function of the gene.
“What we’re finding in animals lacking a particular glutamate transporter is that they have very impaired learning, and sometimes don’t learn at all,” Kavanaugh says.
What’s going on when it’s working? One neuron signals another by releasing glutamate, Kavanaugh explains. The glutamate binds to receptors on the second cell.
When the frequency of glutamate release is increased beyond a certain threshold, something called long-term potentiation occurs.
“Potentiation refers to efficiency of information transfer,” Kavanaugh says, “and that is induced by repetitive activity in the first cell.”
Pavlov’s dog is the perfect example, Kavanaugh says.
A Russian researcher, Ivan Pavlov, did a famous experiment in which a dog came to associate the ringing of a bell with the arrival of food. Eventually, the sound of the bell alone was enough to bring about a behavioral response – the dog began drooling. Pavlov didn’t know it at the time, but he had encouraged new connections to grow in the dog’s brain that linked perception of the bell with the production of saliva.
UM’s Kavanaugh has been studying brain function for 13 years, the first 10 at the Oregon Health and Science University’s Vollum Institute. He moved to Missoula in 2003 because he was already collaborating with other UM researchers, such as Richard Bridges and Sean Esslinger.
“Plus, I like fly-fishing, mountain climbing and skiing,” he admits.
There is so much we don’t know about how the brain functions. “I don’t think we’re in any danger of figuring out how the brain works in our lifetime,” Kavanaugh says.
But the research being done at UM can help scientists figure out how to treat all sorts of disorders. Alzheimer’s, dementia, attention deficit hyperactivity disorder, addictions, schizophrenia – we must understand how the brain normally functions in order to figure out what is going wrong when it misfires.
Other parts of Kavanaugh’s research involve endocannabinoids, recently discovered transmitters that signal through receptors different from the ones used by glutamate. While herbal cannabinoids occur in the cannabis (i.e., marijuana) plant, endogenous cannabinoids are naturally produced in the brains of humans and other animals. Somewhat surprisingly, the receptors for these molecules are among the most abundant in the brain.
One of Kavanaugh’s graduate students, Alicia Awes, recently discovered a new form of long-term potentiation that is mediated by the endocannabinoid system.
In her work, Awes anesthetizes rats and surgically removes sections of brain tissue that are kept alive in artificial cerebrospinal fluid while their activity is monitored using microelectrodes.
“The endocannabinoid system is very complex,” Kavanaugh says, “and there is a lot we don’t know about how it works. We think that Alicia’s discovery of this form of long-term potentiation could be very important.”
The unique form of potentiation, Awes and Kavanaugh explain, expands the role of the endocannabinoid system in plasticity and opens up new avenues of research.
“The importance of endocannabinoids in learning and memory is just beginning to be revealed,” Kavanaugh says. “By understanding their roles in these processes, science will be one step closer to understanding how to treat disorders that impair learning and memory.”
Transverse hippocampal slices. Glutamate transporters. Synaptic plasticity. Endocannabinoids. Long-term potentiation. The words may be big, but the places these research terms maylead is far, far bigger.
— By Vince Devlin