It was one of the most startling brain discoveries in recent history: the finding, announced in 1998, that people keep making new brain cells well into adulthood.
Now, scientists are looking into another surprising idea, that waning and waxing of this brain-cell birthing contributes to depression and the effects of antidepressants.
It's more than an academic question. If it's true, it could help unlock the riddle of just what goes wrong in the brain to bring on the mood disease. And it could help lead to better treatments, like faster-acting antidepressants.
The theory focuses on the hippocampus, a structure deep in the brain that plays a key role in learning and memory. This is where scientists reported finding new cells in autopsied brains from adults in 1998.
The idea that the rate of brain cell birth, called neurogenesis, in the hippocampus affects depression is still in its infancy. It has met skepticism in the field. And even its advocates stress that a decrease in neurogenesis in the hippocampus would clearly not be the only brain change involved in bringing on depression.
So far the evidence for the theory is only sketchy. But it's hard to ignore a pattern in some recent findings in lab animals:
-Stress, which plays a key role in triggering depression, suppresses neurogenesis in the hippocampus.
-Antidepressants, on the other hand, encourage the birth of new brain cells.
-Animals must take antidepressants for two or three weeks before they bump up the birth rate of brain cells, and the cells take maybe another two weeks to start functioning. That's consistent with the lag time antidepressants show before they lift mood in people.
-If an antidepressant is given during a period of chronic stress, it prevents the decline in neurogenesis that normally occurs.
-Exercise, which combats depression in people, also promotes neurogenesis in the hippocampus.
-So does electroconvulsive therapy, popularly known as shock treatment, which works in human cases of severe depression.
Scientists have also found evidence that the hippocampus shrinks in people who have had long-standing depression, although they haven't pinned that on a shortfall in new brain cells. The finding might just reflect shrinkage of existing brain cells instead.
All in all, the evidence shows correlations between reduced neurogenesis and depression, but there isn't a smoking gun demonstrating cause-and-effect yet, says Fred Gage of the Salk Institute for Biological Studies in San Diego.
Gage, who reported the appearance of new brain cells in human adults in 1998, said he suspects a link to depression.
"There are a lot of people working on this," he said. "I think there's no lack of enthusiasm."
Barry Jacobs, a neuroscientist at Princeton University who published the theory with Gage in 2000, said he's now emphasizing the other side of the coin: the possibility that increased
neurogenesis promotes recovery from depression.
"I think there are probably many more things that can plunge a person into depression, and I'm not even sure the critical trigger is this change in the hippocampus," Jacobs said. "Once they've tumbled down into depression, it may be that the change (in neurogenesis) is what keeps them depressed."
The idea, he speculated, is that the shortfall in new brain cells might impair a depressed person's ability to make the mental changes needed to climb back out of the mood disorder.
If boosting neurogenesis really would help people recover from depression, it could give scientists a new target for creating better antidepressants - even if a shortfall in neurogenesis doesn't have much to do with creating the depression in the first place.
Dr. Ronald Duman of Yale University, who studies how antidepressants work and how they spur neurogenesis, said one benefit could be faster-acting medications.
"That's really the silver bullet the field has been looking for," Duman said. "If you have a depressed, suicidal person who comes in for treatment, you don't want to have to put them on a drug for four to six weeks" to get an initial response, especially when the first drug tried might fail to work.
Antidepressants might work in part by spurring neurogenesis in the hippocampus, and that could prove to be one important action to shoot for in new drugs, he said.
Still, Duman said he believes the drugs must exert effects elsewhere in the brain as well. After all, depression brings a bundle of problems - not just low mood, but also abnormalities in sexual drive, eating and sleeping, for example. So it makes sense that several regions of the brain are troubled, and that they all have to change for the disease to lift, he said.
Some brain scientists doubt that brain cell production in the hippocampus contributes to bringing on depression.
Given the known jobs of the hippocampus on one hand, and the symptoms of depression on the other, "it feels like a pretty strange path to get from a hippocampus that's not working very well to increased risk of depression," said Robert M. Sapolsky of Stanford University.
Sapolsky does think there might be a link, but in the other direction: Depression might hamper neurogenesis in the hippocampus. If that's true, he said, it might explain certain memory problems that sometimes appear in depression.
Everybody agrees that new research, and even new research methods, will be needed to demonstrate whether brain cell birthing has anything to do with depression.
Animal experiments provide only imperfect imitations of human depression, notes Dr. Yvette Sheline of Washington University in St. Louis.
She has found that the more time women have been depressed, the smaller their hippocampi tend to be. She's now trying to find a way to measure the amount of neurogenesis in people during episodes of depression.
She warns, though, that studying anatomical brain changes won't completely explain the mystery of what causes depression. The answer will no doubt involve disruptions in how well brain cells function, she said.
Whatever the relationship between depression and brain-cell birth, the whole line of research illustrates an important and under-appreciated fact about the nature of depression.
"This is not self-indulgence, this is not failure of will," Sapolsky said. "This is as biological a disease as diabetes."
© 2002 The Associated Press. All Rights Reserved. This material may not be published, broadcast, rewritten, or redistributed.