Of Mice and Menace
Mice that are too jittery to move away from the wall of a maze, or too nervous to explore new objects in their cage may sound like laboratory rejects. But for researchers hoping to unlock the biological secrets behind human anxiety, they provide great promise.
In three separate studies, researchers from UC San Francisco, Cornell University Medical College and Columbia University have genetically altered distinct strains of mice by disabling a specific receptor for serotonin, a key neurotransmitter in the brain. Low levels of serotonin have been associated with depression and obesity, while high levels have been linked to anxiety.
The receptor, called 5HT-1A, blocks serotonin activity in the brain.
Although scientists have known that the 1A receptor is somehow linked to human anxiety and depression, they do not fully understand how it works. Researchers hoped to shed some light on the receptor by knocking out its gene--effectively increasing serotonin activity--and seeing what would happen.
So what are these “knockout” mice like? Dr. Laurence Tecott, professor of psychiatry and head of the research at UC San Francisco, described how his mice stuck to the sheltered sections of a ring-like platform raised 16.8 inches off the ground. When placed in a brightly lighted box, they hugged the walls instead of taking center stage.
The knockout mice were even reluctant to approach a benign pingpong ball placed in a corner of their cage. In all cases, the 1A knockouts were less willing than their unaltered littermates to venture out and explore their surroundings.
In the world of mouse research, these are sure signs of anxiety.
Each group of researchers was initially unaware of the parallel experiments being done by their peers. But in all three studies--published within four months of each other in the Proceedings of the National Academy of Sciences late last year--knocking out the 1A receptor triggered the same behaviors. The similar results strengthen evidence of the connection between the altered gene and anxiety, said Linda Brady, chief of neuropharmacology at the National Institute of Mental Health, which provided funding for the study at Columbia.
But what does a reserved rodent have to do with human feelings of anxiety? A lot, it seems. At least on the molecular level.
Jay Gingrich, research fellow at Columbia, was part of that university’s knockout study, headed by Rene Hen. “Some people [are skeptical] about what we can learn from animal models,” he said. “It’s not intuitively obvious to people. Mice have fewer neurons than us, but they have all the same basic structures.” Nevertheless, Gingrich cautioned, there are limitations to the types of conclusions that can be drawn at this point. “I think the key thing to bear in mind is that [by knocking out the 5HT-1A receptor] we’re not mimicking a known human mutation,” he said.
Tecott is equally cautious. “We’re not saying that anxious people are anxious because they’re missing the 1A receptor,” he said, noting that any therapeutic applications stemming from this research would take many years to develop.
He said the serotonin system is so complex that one receptor alone cannot explain why some people are more anxious than others. Scientists have compared the role of one receptor in the brain’s serotonin system to the sound a single musical instrument produces in an orchestra. One instrument playing off key can affect the intonation of a whole symphony.
Understanding how specific receptors work could enable a degree of fine tuning in treatments not possible decades ago.
Advances in genetic engineering, molecular biology and neuroimaging have made animal models increasingly relevant in human behavior research. Dr. Jeremy Coplan, associate professor of clinical psychiatry at Columbia, called knockout mice “a quantum leap in biological technology.”
Another expert, Dr. Charles DeBattista, assistant professor of psychiatry and behavioral sciences at Stanford University, noted that “the process of developing knockout strains of animals is becoming more pervasive in psychiatry.”
Research Provides Target to Examine
The benefits of zeroing in on specific receptors include the potential expansion of treatment options for the estimated 19 million people suffering from the debilitating effects of anxiety disorders in the United States. Anxiety disorders go beyond the mere concern over a final exam or office deadline, and include phobias, post-traumatic stress disorder and obsessive-compulsive disorder.
“This [research] is giving you a target to look at,” said Brady of the National Institute of Mental Health. “We can use that target to look at the progression of disease over time. We might learn why some patients respond to a particular treatment and others don’t.”
Drugs such as Prozac act indiscriminately on all the serotonin receptors--there are at least 14--and boost the levels of serotonin in the brain. “A drug like Prozac works like a shotgun,” said Coplan. “It hits all [serotonin] receptors everywhere.” Homing in on a particular subtype, he said, would be like putting a “sniper behind that shotgun.”
Prozac can also cause unpleasant side effects such as nervousness and sexual dysfunction. Researchers hope that by developing drugs that can target a specific receptor, such side effects will be reduced.
One drug that partially acts on the 1A receptor, buspirone, is already on the market and has shown promise in treating both anxiety and depression. But mental health advocates say that for all the research and the psychiatric medications being developed, comparatively little is known about how the human mind works with the human body.
“I see it right now as a raindrop in a storm,” said Mary Guardino of the mice research. Guardino is executive director of Freedom From Fear, an advocacy group she founded after enduring two decades of depression, panic attacks and agoraphobia. “It’s important to emphasize that this research is only in its infant stages. I wish it would go faster. It’s not like research in areas of medicine, like cancer or even AIDS, because they have tangible mechanisms to work with.”
Other advocates agree, hoping that the genetic and biological research will help take the stigma away from mental disorders.
“I think that across the board, the American public misunderstands mental illness and its treatment,” said Michael Faenza, president and chief executive of the National Mental Health Assn. “When a doctor suggests an antidepressant, ideally the patient would react in the same way as if they had received an antibiotic or a treatment for blood pressure.”
If it takes more strains of nervous mice to help achieve that goal, so be it, say the advocates.
Faenza said he hopes that any research establishing mental illness as a disease--comparable to such physical ailments as diabetes or cancer--will lead to greater acceptance of its sufferers in our society. “I’ll look forward to the day when breakthroughs in genetic and biological disorders create a big impression in society’s mind about what’s a disease and what’s not a disease,” he said.
