Researchers studying animal models for depression have uncovered new clues to its neurobiological underpinnings, why antidepressants’ effects are delayed and why some people are more resilient to depression even in the face of major stress. These insights, from two recent papers from Eric Nestler’s research laboratory at the Mount Sinai School of Medicine in New York City, build on a long-standing but still imperfect science of depression modeling in rodents.
The first paper, published in Nature Neuroscience in February, revealed that different molecular mechanisms mediate two abnormal emotional behaviors seen in rats—anxiety and anhedonia (decreased ability to experience pleasure)—and shed light on the intracellular pathways involved. In the study, normal rats were raised in isolation, a “passive” model of stress that Nestler argues is relevant to certain types of human depression.
The second report, in July’s Journal of Neuroscience, suggests a potential reason that antidepressants, when they are effective, work only after prolonged treatment: by regulating which genes are switched on or off in the nucleus accumbens, a collection of neurons known to be involved in pleasure and reward. The study found that similar regulation occurs naturally in resilient mice that do not develop depression-like behaviors despite exposure to the same stress as other animals—in this case, being repeatedly exposed to more aggressive mice, an “active” stress model known as social defeat that scientists have studied extensively.
Specifically, the researchers found what they say is a striking degree of overlap in patterns of gene expression among resilient mice and mice treated with imipramine, an antidepressant. They said their findings raise the possibility that people who are resilient to depression may naturally mount antidepressant-like adaptations when faced with chronic stress.
Researchers have identified psychosocial characteristics associated with resilient people—including optimism, spirituality and religion, and strong social support networks—and the U.S. Army recently announced a program to provide resiliency training to all of its soldiers and officers in an attempt to stave off a rising tide of diagnoses of psychiatric disorders among troops returning from combat. The Nestler work is one of the first studies to try to unravel the molecular biology that underlies resilience, opening new avenues of study for animal models of depression.
Animal Models’ Weaknesses
Taken together, the papers advance a debate among scientists about the relevance of using animal models as a stand-in for human depression, which can manifest as a wide range of symptoms in different people.
“ ‘Depression’ describes a rather vague collection of behavioral abnormalities that can be very different from one person to the next,” says Nestler. “It is a syndrome, not a disease—a heterogeneous collection of many different etiologies,” or causes.
During the past few decades, researchers trying to understand human depression have applied various stressors, acutely or chronically, to rats and mice to try to elicit depression-like behaviors. The test of these models’ validity has been whether administering an antidepressant alleviates behavioral responses to each stressor.
Among the problems with these models is that rodents cannot say that they’re feeling depressed. Researchers must rely on behavioral clues to infer depression—such as giving up during a test in which they are forced to swim. Such behaviors are signs of what scientists call learned helplessness, long considered the classic animal correlate to human depression. But in recent years, questions have arisen as to whether such behaviors are merely an adaptive response to the stress, rather than a valid marker of depression.
“Learned helplessness is falling out of favor among some researchers,” says David Lyons, a Stanford University neuroscientist who studies stress responses in animals. That’s in part because it is not normally long-lasting and therefore has limited value for testing chronic antidepressant treatment, he says.
A second problem relates to relying on the action of antidepressants in rats and mice to validate that the test is truly modeling depression, since current antidepressant medications are ineffective or only partially effective in up to half of people who take them for depression. Moreover, all antidepressants on the market were tested using the same stress models that they are now used to validate, a quandary that has stymied advances in depression treatment.
“The field of depression has been sort of stuck for a few decades because it’s been difficult to break out of these few paradigms,” says Nestler.
Stress Effects ‘Not Always Reliable’
Consistency and replicability also challenge scientists. Even in the hands of seasoned researchers, many of these stress-induction methods do not reliably elicit depression-like behaviors in all, or even most, animals. Nestler, for example, says his team has never been able to elicit signs of depression using a model that subjects animals to repeated mild stress such as physical restraint, though some labs have.
Athina Markou, a behavioral pharmacologist at the University of California, San Diego, also has been unable to replicate depressive behaviors in chronic stress models. “Stress effects are not always reliable in animal models, and we don’t know why,” she says. “This has been a huge setback in the field that people are not really discussing.”
Part of the problem, Markou believes, is that—despite common belief—there is little evidence in humans to support the notion that life stress leads to depression. “There has been a lot of speculation over many years that stress impacts depression, but when you look closely at the (scientific) literature, there are virtually no data to support that hypothesis,” Markou says.
One of the few studies that showed a link, she says, was an Emory University study that tracked depression rates in an urban population that had been exposed to traumatic events such as being threatened with a gun or having had a loved one killed violently. “That is the only evidence I know of where there is actual data showing that stress leads to depression,” she says.
George Bonanno, a Columbia University psychologist, has argued that resilience—not depression or anxiety disorders—is the most common outcome among people who have faced traumatic events in their lives.
Lyons, Markou and Nestler agree that individual variations in resilience or susceptibility to stress may be one reason reliably reproducing depressive behaviors in rodents exposed to stress has been so difficult. The work by Nestler and colleagues in two different stress models is significant, Markou and Lyons say, because it reveals potential molecular mechanisms that could explain contradictory results and suggests a possible therapeutic target for increasing resilience. To Nestler, the findings also underscore the importance of using multiple rodent models to investigate depression.
“We need to be flexible,” says Nestler. “Human depression is not a single entity, so there is no way that a single model is going to replicate all of human depression. Each of these models is offering something.”