Associate Professor Rick Bridges, left, and Professor Charles Thompson study key signaling molecules in the brain such as glutamate, modeled above.

Corridors of the mind

UM Research Seeks to Understand How the Brain Talks to Itself

Imagine not being able to speak. Or to think “sweetheart” but say “mud puddle” instead. Imagine not being able to move your arms or legs. Or not recognizing your son across the dinner table. Imagine being swept away in an electrochemical brainstorm, disconnected from the outside world for an unknown length of time.

The central nervous system--our brain and spinal cord--is so complex and well-balanced that it only takes a small error to produce the profound effects of stroke, Alzheimer’s disease, epilepsy or the irreversible degeneration of amyotrophic lateral sclerosis. Understanding how the nervous system works and what happens when it goes wrong, whether from disease, injury or an unfortunate roll of the genetic dice, will be one of the central problems for science in the next century, according to Associate Professor Richard Bridges of the Department of Pharmaceutical Sciences in UM’s School of Pharmacy and Allied Health Sciences.

Our Nervous Systems, Ourselves

“We are all interested in how the brain works,” Bridges says “because it speaks to the essence of who we are.” While other medical conditions can affect us deeply--and can even be life threatening--they do not alter our central selves. Neurological disorders, however, fundamentally change our personalities and the way we perceive and interact with the world.

As Bridges puts it: “Everything that makes us human is related to the nervous system.”

At UM a growing number of researchers are at work on diverse aspects of the central nervous system--from the neurochemistry of reproductive hormones to the efficacy of certain plant extracts as remedies for headaches and migraines. Their studies primarily focus on how brain cells talk to each other via chemicals called neurotransmitters and how this specialized signaling process can be disrupted by disease or injury. It turns out, Bridges says, that the same mechanisms by which neurons communicate also are the mechanisms affected by drugs and environmental toxins.

Susan Queen, assistant professor of physical therapy, in her lab.

By taking a pharmacological approach to understanding the nervous system, UM researchers are learning more about how the system works at its most basic level and what the consequences are when something goes wrong. At times, Bridges says, abnormal functioning can lend insight into normal function. “Often a drug will have a positive effect on a disease, but we don’t know how it works,” he says. “If you can figure that out, you will have a better understanding of the underlying mechanisms of brain cell communication.”

Like the central nervous system itself, neuroscience research at UM branches out in many directions, connecting the pharmaceutical sciences with psychology, physical therapy and the many subdisciplines of chemistry and biology, even geology and ecology. And, like individual nerve cells, faculty members provide constant feedback to each other, influencing the overall direction of research.

“I feel very lucky to be working here at this particular time,” chemistry Professor Charles Thompson says. “Thanks to computers we have the capacity to visualize the brain down to its atoms and molecules so we can share our understanding across disciplines. Everyone has something to bring to the table.”

As an organic chemist, Thompson tries to build his understanding of brain function atom by atom, hoping to discover ways to correct problems in brain chemistry. In his view custom-designed drugs will be the surgical tools of the future. “If you think about the field of mental health even twenty years ago,” he says, “the drugs available now--like Prozac and lithium--help people function much better than surgery or electroshock therapy ever could.”

Physical therapist Chad Kay, M.S. ’98, helps Erna Rae, a patient in stroke rehab.

Glutamate: The Good, the Bad and the Destructive

One brain chemical in which Thompson, Bridges and several other UM scientists are particularly interested is the neurotransmitter glutamate--the same compound found in the common food additive monosodium glutamate and an amino acid essential to the proper working in every cell of the body. In a properly functioning nervous system, neurotransmitter signals that stimulate neighboring neurons to repeat a message are balanced by signals that inhibit neuron activity. Glutamate is the most common excitatory neurotransmittor in the brain and is essential to our being able to learn and remember. It also plays a fundamental role in how our central nervous system adapts to the changes brought about by growth and development, learning, injury and aging.

Although enough glutamate is essential for proper brain function, too much causes neurons to keep signaling and can literally stimulate cells to death. Strokes, head injuries or the progressive changes brought about by certain diseases cause cells in the central nervous system to leak glutamate into the tiny spaces between them. In healthy cells, special protein molecules--like mop-up crews--actively transport excess glutamate out of intercellular spaces, moving it back into cells where it can be safely warehoused. When cells are damaged, these transporter molecules don’t work well. Or they work in reverse, pumping glutamate out of cells and allowing it to build up to toxic levels in the intercellular spaces, which increases the damage and decreases chances for recovery.

“If the body is creating a surplus of glutamate, it would be helpful to find a molecule that slows down or blocks this surplus,” says Thompson. “Or if we can’t stop glutamate from leaking out of cells, can we somehow find something that acts as a molecular plug?”

Exploring the Mysteries of Transporter Molecules

In order to understand how transporter molecules work, Bridges and Thompson make inhibitors. Inhibitors are molecules that either look similar to glutamate and fool the transporter into moving them, or molecules that act as chemical plugs, binding with the transporter proteins and taking them out of service.

Models represent the nine stable configurations of glutamate in solution and the starting point for researchers seeking to understand how the molecule binds with others in the brain.

“By finding different chemicals that interfere with the transport process,” undergraduate research assistant Ben Mickelson explains, “we can learn how the transporter proteins work.” This knowledge will help researchers understand the role of these transporter proteins in certain diseases or conditions.

According to Bridges, there are four or five different types of transporter molecules present in brain cells. The transport inhibitors developed at UM are being used by researchers at other institutions working on particular central nervous system diseases or injuries. The next step for researchers will be to develop drugs that can selectively regulate the different transporter molecules to determine whether one type is more involved in brain cancer, for example, or a stroke.

Reducing Stroke Damage

“When a stroke occurs, the initial insult is localized,” says Pamela Meck of St. Patrick Hospital in Missoula. “But because more of the neurotransmitter is being released from cells deprived of oxygen, you get additional brain injury that spreads out from the original site. A stroke that is as big in volume as a tablespoon could become more than three ounces big three days later. Nothing can make the initial damage go away, but if you can reduce the total volume of damaged tissue, you can reduce the extent of damage to the brain and improve people’s recovery time.”

Meck is the clinical research coordinator for the Montana Neuroscience Institute, a collaboration between UM and St. Patrick Hospital. She has been overseeing the hospital’s participation in a national trial of a drug designed to limit the spread of secondary damage following a stroke. In preclinical tests, she says, the drug--which does not work directly on glutamate, but on a related neurotransmitter--was shown to reduce stroke-damaged tissue by 80 percent if given within one hour of the first stroke symptoms, by 50 percent if given within six hours.

The problem, Meek says, is that many people who have strokes either do not realize what their sudden weakness, blurred vision, speech difficulty, dizziness or inexplicable headache might mean, and they wait a day or two before coming to the emergency room. “There is still the misperception that if you have a stroke you will either die or that’s as bad as it will get,” she says. “That is not true. It would be great if we could stop the secondary damage in the early stages so the effects are not so catastrophic.”

The same thing that happens in stroke also happens in spinal cord injuries, according to Susan Queen, an assistant professor of physical therapy. Initial damage from a fall or other injury is only the beginning. As a result of the injury, excess glutamate released from nerve cells in the spinal cord kills more cells. In addition, other biochemical changes occur that lead to the presence of oxygen atoms--free radicals--which continue to damage cell proteins, such as the glutamate transporters, cell membranes and DNA.

Queen has spent nearly twelve years researching the glutamate system in a variety of neurological conditions, including traumatic brain injury, fetal alcohol syndrome and cyclosporine neurotoxicity or damage to the nervous system by a certain kind of immune system suppressant. Since joining the UM faculty in 1996, Queen has been studying how injury to the spinal cord affects the number of glutamate transporters present that can help get rid of excess glutamate. She thinks that if transporters are affected by an injury and a way could be found to minimize damage to the transporters, then damage to the person also could be minimized. “In repairing the central nervous system,” she says, “there would be a smaller tissue gap to be bridged.”

Bridges, Thompson, Queen and dozens of other UM faculty members and students make up the growing number of researchers working to unravel the mysteries of brain and central nervous system communication. Their daily routines in the lab and in the classroom--their collaboration and unity of purpose--demonstrate the general direction of science today, and they will help us understand who we really are.

"We not only have found a terrific environment in which to build a competitive neuroscience program," Bridges says, "but I think we all get a kick out of surprising people with the reality that faculty and students at UM are actively contributing to such cutting-edge fields as brain function and neurodegenerative disorders."