Severe stress, whether sudden, like a car bomb, or sustained, like a hostile environment, can have serious consequences for mental health, including depression, post-traumatic stress disorder (PTSD) and substance abuse. But only some are affected. “Even under horrendous stress, only 10 to 30 percent of people have problems,” says Eric Nestler, professor and chair of neuroscience at Mt. Sinai Medical Center in New York and a member of the Dana Alliance for Brain Initiatives.
Why not everyone? The riddle of resilience—the ability to cope successfully with highly stressful situations—has become a focus of research in recent years. “The thought is, if we could understand why some people don’t develop psychopathology, it would give us new clues for treatment, or therapy to build up [protective] factors that relate to resilience,” says Dennis S. Charney, dean of the Mt. Sinai School of Medicine.
While some scientists, like Charney, study people who have come through harsh experiences like combat or prolonged mistreatment in POW camps to see what psychological qualities make them special, others, like Nestler, are looking at the neurobiological underpinnings of resilience in laboratory animals and cell cultures. And researchers have combined findings from animal and human studies to identify neural circuits and brain chemicals that may determine the ability to survive stress with mental faculties intact.
A key ingredient
Now Nestler and his team have delved more deeply into the neurobiology of the reward circuit, a brain area known to be involved in substance abuse, depression, and PTSD, and identified what may be a central molecular pathway on the road to resilience.
In the study, published on May 16 in Nature Neuroscience, the researchers subjected mice to chronic stress and separated them into those that displayed depression-like behavior and those that seemed to be resilient. When they examined their brains, they found increased levels of the compound ΔFosB in the nucleus accumbens—a keystone of the reward circuit—only in the resilient mice. ΔFosB is a transcription factor, which binds to DNA of certain genes to regulate their activity.
Further experiments confirmed the role of the chemical: Mice genetically engineered for extra ΔFosB were resilient in the face of stress, while those bred to produce a chemical that antagonized ΔFosB showed many depression-like symptoms.
The researchers also showed that conditions like prolonged social isolation, which makes the mice more vulnerable to stress, reduced levels of ΔFosB; and that the antidepressant fluoxetine, which reverses depression-like symptoms, increased it.
Whether the compound plays a similar role in humans is uncertain—it’s impossible, with current methods, to measure it in living organisms. But early findings point that way: postmortem studies found 50 percent less ΔFosB in the nucleus accumbens of people who had been depressed than in a control group.
“This is an important step forward, “ says Peter Kalivas, professor and co-chair of neurosciences at Medical College of South Carolina. “[Nestler] has identified a molecular sequence of events that supports resiliency—that’s new. It pushes resilience work into the cellular dimension.”
Kalivas has worked with the neurobiology of addiction, and he speculates that further studies may reveal convergence of the two areas. “If baseline levels of ΔFosB are higher, are you less susceptible to being addicted? I don’t think this question has been asked yet, but if you developed strains of mice in which some are more prone to addiction than others, I wouldn’t be surprised if you found the less susceptible ones had more ΔFosB in the nucleus accumbens.”
Kalivas points out that ΔFosB represents a sort of “middle ground” in whatever cellular pathway supports resilience. “We have to figure out what ΔFosB is doing to regulate proteins.”
Toward this end, Nestler’s research team is looking more closely at the genes that bind to ΔFosB. They have identified a protein that reduces activity of certain glutamine receptors, and shown that this change may promote resilience in mice. ΔFosB also regulates a gene that influences synaptic plasticity, which could, they speculate, counteract the negative learning associated with stress.
The road ahead
Right now, Nestler says, he and collaborator Gabby Rudenko of University of Michigan are involved in a screening project to identify drugs that activate or potentiate ΔFosB, funded by the American Recovery and Reinvestment Act of 2009.
The screening process involves adding purified ΔFosB to test tubes with a DNA sequence that normally binds to it, then observing how different compounds affect the binding process.
Testing random compounds for the one that activates ΔFosB is “like looking for a needle in a haystack,” says Laurie Nadler, chief of the neuropharmacology program at NIMH—an impossible task, really, if not for automated equipment that can vet hundreds of thousands of molecules quickly.
Screening for a ΔFosB-active molecule will also be done at the Broad Institute of Harvard and MIT, using the “small molecule repository,” a collection of over 300,000 compounds that the NIH provides to a network of laboratories for just such projects. "This is part of the NIH-wide Molecular Libraries initiative,”says Nadler.
Finding candidate molecules is just the first step in a lengthy process, she says; it is generally followed by “tweaking” their chemical structure to enhance desired properties (like cell penetration), and testing them in cell culture and then in animals. The ultimate goal: novel drugs to treat human diseases.
It’s a distant hope. Screening and testing are complex and painstaking, and blind alleys are common. To complicate matters, transcription factors like ΔFosB are an unusual target. They act inside the cell nucleus; to interact with them a drug must penetrate two sets of membranes. (Most drugs bind to molecules, like receptors, on the surface of the cell.)
These obstacles can be overcome, says Nestler. “Any drug that affects the brain must get through the blood brain barrier, and the same feature would enable it to penetrate cell membranes. Most transcription factors don’t make good drug targets because they are made in every cell; what makes ΔFosB appealing is that you only see appreciable amounts of it in the one brain region.”
Still, “it would be naïve to expect a medication at the end of this project,” he says. A more feasible ambition might be a biomarker for ΔFosB—a molecule that binds to it, allowing reseachers to track the compound in living tissue.
“An immediate use for such small molecules would be as a research tool to better understand the function of ΔFosB in the brain, in stress and depression and drug abuse,” says Nadler. “They could ultimately be useful in brain imaging, to look at ΔFosB levels as a potential marker for severity of disease, or for response to antidepressant therapy.”
This could open a potentially productive new chapter in the ongoing interchange between human and animal resilience research, according to Dennis Charney. Levels of ΔFosB in human brains might be correlated, for example, with qualities—like optimism, positive emotions, and a sense of purpose in life—that have been linked to resilience by psychosocial research, and the transcription factor might be measured in people who have demonstrated unusual resilience in the face of stress.
“What Eric is doing, identifying biomarkers and signaling pathways, could not have been done in human studies; but you can’t evaluate complex things like optimism in animals, or treat them with psychotherapy,” says Charney. “[We] have a joint lab meeting once a month—my group does all human studies—to talk about how we can move back and forth. It’s really forward and reverse translational research.”