Can chronic stress cause depression? A new study in mice adds important evidence that it can, and sheds light on how antidepressants work.
The new research, published in Nature, builds on earlier studies showing that chronic high stress kills neurons and prevents neurogenesis — or the birth of new brain cells — in a region called the hippocampus. Neurogenesis in the hippocampus seems to be necessary for a healthy stress response.
Led by Heather Cameron, chief of neuroplasticity at the National Institute on Mental Health, researchers compared normal mice to so-called v-TK mice. These are mice that researchers engineered to be unable to undergo neurogenesis in their hippocampus as adults.
Researchers tested the animals’ physiological response to a stressor — in this case, being restrained for 30 minutes. The v-TK mice had elevated levels of stress hormones 30 minutes after being restrained, compared with normal mice, suggesting that the engineered animals were less able to recover from the experience.
“We found that when we stress the animals and remove the stress, they have a stress response that lasts longer,” says Cameron.
The researchers also examined the animals’ behavioral response to stress. In one test, hungry mice were placed in an open, unfamiliar field. This situation is frightening to rodents, since it leaves them feeling vulnerable to predators. A food pellet was placed in the center of the field. Both normal and v-TK mice approached the food cautiously, taking the same amount of time to work up their courage.
But when the mice were first placed in restraint for 30 minutes before being exposed to the field, the v-TK mice showed symptoms of depression — in this case, food avoidance in an unfamiliar environment — taking much longer than the normal rodents to snap up the food pellet. Stress didn’t affect the response time in normal mice.
In another test in which the mice were forced to swim in an inescapable plastic cylinder, the v-TK mice gave up and stopped swimming much sooner than normals: another depression-like symptom, which past research has shown can be reversed with antidepressants.
“I think the findings fit well with the idea that stress can cause depression or that stressful situations can precipitate depression,” says Cameron.
In another test for anhedonia, or pleasurelessness, a hallmark symptom of depression that often leaves people feeling hopeless and inconsolable, the mice were given the choice between plain water and sugar water. Healthy mice love sugar and will naturally drink a great deal of sugar water, which they did in the current study. But the v-TK mice said meh, sticking with plain water.
“Sucrose preference in animals is thought to be related to [pleasurelessness] in humans. People who are depressed take less pleasure in things that used to be pleasurable for them,” says Cameron.
These animal tests for depression are the same ones that are used to investigate the efficacy of antidepressant drugs and to determine whether they should be further tested in humans. Effective antidepressants reliably reverse these depressive behaviors, and previous research has also shown that they encourage neurogenesis in the hippocampus, reversing stress-induced damage in that region. (Electroconvulsive therapy has also been shown to have the same effect.)
In fact, the first study to connect neurogenesis to depression was a study of antidepressants, which found that the drugs stimulated the growth of new cells in the hippocampus. The second major study to support the hypothesis, conducted by Rene Hen, director of the division of integrative neuroscience at the New York State Psychiatric Institute, and colleagues, found that blocking neurogenesis dramatically reduced the effects of antidepressants.
“I think our work indicates that we are on the right track with antidepressants,” says Cameron, whose study was funded by the government, not the pharmaceutical industry. “Since we found this link that has nothing to do with antidepressants and suggests that the neurogenesis hypothesis really does seem to be valid, and since we already know that antidepressants [promote neurogenesis], our results support the idea that antidepressants [have real effects].”
(It is not known whether talk therapy affects neurogenesis in humans — and it’s impossible to do talk therapy with rats — but animal research does suggest that providing a better social and physical environment helps promote the growth of new brain cells.)
Interestingly, inhibiting neurogenesis in mice appeared to worsen their response primarily to psychological stress, involving fear or social defeat rather than actual pain or injury. In the restraint and forced-swim tests, for example, the mice aren’t hurt, they just fear that pain or worse may be coming.
Earlier research has also shown that in mice that exhibit depressive symptoms, their response to physical stress — bleeding, anesthesia or cold — is normal. In the current study, when researchers subjected the v-TK mice to anesthesia, their stress-hormone levels responded normally.
“It’s an interesting paper that does two things: it confirms prior findings that neurogenesis in the hippocampus influences [a key stress system in the brain] and therefore the production of stress hormones,” says Hen, who was not associated with the study. “The novel part is that it links this with behavioral changes that take place in response to acute or chronic stress.”
Of course, the loss of neurogenesis is not the only cause of depression, nor is recovery of this function the only way to treat it. Otherwise, antidepressants would work for everyone, which they don’t, and blocking neurogenesis would completely eliminate the benefits of the drugs, which it doesn’t. The mechanisms of depression are certainly more complicated.
“Depression is very heterogeneous,” says Hen, noting that the complexity of the disease helps explain why antidepressants may sometimes appear no better than placebos in clinical trials.
About 30% to 50% of people in clinical trials don’t respond to antidepressants, Hen says. That gives the false sense that the overall response to the drugs is very small. But if you look at the populations of responders and non-responders separately, you see that “the ones who respond actually truly respond,” he adds.
Another question raised by Cameron’s study is why the brain would respond to stress by killing brain cells and making itself more sensitive to future stress. “One way to think about neurogenesis is that it’s a process in the brain that allows you to adapt to changing environments,” says Hen. “In stressful environments where you have lower neurogenesis, this may be adapting to the fact that when you are in a stressful situation, it’s better to stay put.”
“If you’re in a very dangerous environment, it probably is adaptive to not want to go out and seek new experiences. It’s probably best to stay close to home and lay low and focus on survival,” says Cameron.
“That’s the normal function, but if that process becomes exaggerated you can [see how] it would become maladaptive,” Hen says.
Perhaps the new findings will help researchers develop better treatments for the 20% of people with depression whose disease fails to respond to any current treatment.