Feeling of Hopelessness May Be a Simple Short Circuit

Mental illness poses a particular challenge for medical researchers trying to understand what is going on in patients' brains. Exploratory surgery is a tough sell.

Instead, researchers turn to animal models of psychiatric ills, bearing in mind that a mouse will never show signs of hypochondria and a fruit fly will never buzz off to Vegas for a gambling addiction. Still, researchers have made headway against a lot of psychiatric ills by experimenting on animals, and a neuroengineering team led by Stanford University's Karl Deisseroth reports on a possible answer to one of the mysteries behind depression.

"Depression raises all kinds of questions," Deisseroth said. "It has all sorts of symptoms and responds to a variety of drugs that act in different ways." Almost 15 million people nationwide suffer from a "major depressive disorder," according to the federal National Institute of Mental Health.

The researchers looked at a rat known for exhibiting a symptom of depression — hopelessness. "They give up on tasks easily," he said. The same rats respond to treatment with fluoxetine, an antidepressant commonly given to people as well. The team treated some of their rats to five-to-seven weeks of stress, such as changing their sleeping and feeding schedules, tilting their cages and using strobe lights. Some of the rats received antidepressants and some didn't.

To measure the rat's hopelessness, the team then dunked them in water for a swimming test and loosed them in an open sandbox, very scary for rats. Then they did the tough sell part of their science, decapitating the rats and slicing up their brains, specifically a part called the hippocampus that has been tied to depression in past research. Researchers have observed shrinkage of the hippocampus in animal models of depression ranging from rats to tree shrews.

The team hooked the slices of rat hippocampus to a novel electronic circuit test called "voltage-sensitive dye imaging" that let them watch electrical circuits fire across the still-living brain tissue of the rats. (The tissue lives on for about five hours after death.) They found that in depressed rats, electrical circuits just died out in the hippocampus slices. "A lot like a river just flowing into a desert and petering out," Deisseroth said. Nonhopeless rat brains just sent the circuit straight through, as did the samples from rats treated with antidepressants before their demise.

Essentially the study — published online by the journal Science — suggests that hopelessness is just a short-circuit of a healthy process in the brain. "People may have genes, or life events, or other factors behind the short circuit, but it may all be tied to a common mechanism," Deisseroth said. Analysis suggests that antidepressants may help new brain cells grow in the hippocampus, allowing the circuit to connect, the study concludes.

For researchers looking for new drugs to treat depression that may be a key insight, he argues further. Researchers should just look for ways to fix the hippocampal circuit, rather than concentrating on individual causes behind its disruption, if the team's findings applies to people.

And while people likely won't volunteer for the hippocampal slicing analysis, improvements in medical imaging may allow researchers to view electrical brain circuits in coming years in sufficient detail to repeat the rat experiment. "Once we know all that, we can look at more targeted therapies for depression," Deisseroth said.

"It is important to note as we do in the paper that this is only the first step in probing depression circuitry with high-speed imaging, and we are cautious in our interpretations because there is much more work to be done to probe the possible convergence of other life experiences and treatments and genes on this and other brain circuits."