The Neurobiology of Resilience

Active Molecular Mechanisms Counterbalance Vulnerability to Stress-Related Depression and Anxiety Disorders
by Brenda Patoine

July, 2014

 BRIEFING PAPER

Ann Whitman                                                                         
(212) 223-4040
awhitman@dana.org

What makes one person more resilient to stress than another? How do some people seemingly take even extreme stress in stride while others succumb to depression or anxiety disorders when faced with trauma or tragedy? Might differences in brain structure or function explain it?

These are questions that have been tackled by social scientists for decades, resulting in a fairly comprehensive description of the kinds of emotional and behavioral characteristics that tend to describe a “stress-resilient” person–things like optimism, a strong social support system, an ability to find purpose in life, or a grounding in faith or spirituality. A “glass-half-full” kind of person.

More recently, neuroscience has tackled the question of resilience, with the goal of understanding what underlying neurobiological mechanisms might contribute to resilience in humans so that more targeted, more potent interventions can be developed. While treatment breakthroughs have been elusive, recent work has begun to shed new light on the resilient brain.

Eric Nestler, M.D., Ph.D., professor and chair of neuroscience at the Icahn School of Medicine at Mount Sinai in New York City and a member of the Dana Alliance for Brain Initiatives, has made the study of resilience a primary focus of his neuroscience research. “The question of what drives resilience neurobiologically or genetically has been really hard to get any kind of a handle on,” he says.

Part of the problem, Nestler says, is that there is a divergence in the field between studies in humans and studies in animals. Human studies are constrained by the kinds of methodologies that are possible in human subjects, essentially limited to brain imaging or peripheral hormone measures. Animal studies enable researchers to explore underlying mechanisms more deeply, but questions remain about their relevance to the human condition. This is true in many research areas but especially in psychiatric disorders like depression or anxiety, because rodents can’t tell us how they feel.

Nevertheless, animal models of stress have contributed valuable insights about the neurobiological mechanisms underlying resilience. These insights are helping scientists inch down a path that may eventually lead–most likely later rather than sooner–to the first truly novel drugs for depression and anxiety in half a century.

The social-defeat model is perhaps the best studied of the animal stress models. Developed by Nestler and colleagues when he was at University of Texas-Southwestern, it entails placing a mouse in physical contact with a more dominant aggressor mouse for a few minutes a day, and then housing the mouse behind a screen in the same cage as the aggressor for the rest of the day. The mouse is therefore exposed to all of the sensory cues of the aggressor but without physical contact. In other words, the mouse is seriously stressed out.

This is repeated for 10 days, after which most mice exhibit a well-characterized syndrome of behaviors deemed comparable to depression in humans. Yet somehow, about a third of the mice do not. These are the resilient ones, and they have been a major focus of investigations to understand what is different about them.

Resilience as a ‘Failure of Plasticity’
Looking back at this ongoing body of research, Nestler says: “The most important and interesting principle is that resilience is not a passive process. It’s not that the mice that are resilient simply don’t show the bad effects of stress that are seen in susceptible mice. Some of those kinds of changes are seen, but by far the most predominant phenomenon is that the resilient mice show a whole additional set of changes that help the animal cope with stress.”

Resilience, Nestler says, is a very active process. In fact, he says, “One might conceive of susceptibility to stress as a failure of plasticity.”

A recent paper published in Science by Ming-Hu Han, Ph.D., and colleagues is a beautiful example of the neurobiology of “active” resilience. Han, an assistant professor in pharmacology and systems therapeutics at Mount Sinai’s Icahn School, found in earlier work using the social-defeat model of stress that global gene expression was vastly different in resilient vs. susceptible mice. For every 100 genes that changed, either up or down, in susceptible mice, 300 genes changed in resilient mice, he says.

“This was a very interesting finding because it means that resilient animals are not actually insensitive to stress, but rather are actively using more genes during stress,” says Han.

To try to figure out why this was the case, Han and his team investigated the firing activity of dopamine neurons in a particular area of the brain associated with depression symptoms, the ventral tegmental area (VTA). They found a much higher rate of firing in dopamine neurons of depression-susceptible animals compared to resilient ones. So they dug deeper into the molecular circuitry of the VTA, and found that the neuro-electrical current running through one particular ion channel, called the Ih channel, was markedly increased as well–neatly explaining the increase in neural firing.

To the researchers’ surprise, however, they found that this same Ih channel was even more greatly increased in resilient mice, even while dopamine neuron activity remained normal. This was puzzling.

“How could this increase in the Ih channel, which we know is a pathogenic mechanism, be even bigger in resilient animals?” Han asked. “This meant that there definitely had to be some other mechanism that counteracts this bad change in the Ih channel.”

Eventually the researchers found another circuit, a potassium channel that mediates the Ih channel’s increase in resilient animals only. The stress-induced increase in Ih, an excitatory channel, was effectively counterbalanced by an increase in the potassium channel, which is inhibitory. When the Ih channel’s excitatory activity reaches a specific “tipping point,” Han says, the compensatory action is triggered, normalizing dopamine neuron firing in resilient mice. This work suggests a clear neurobiological mechanism underlying resilience and elegantly demonstrates the active nature of resilience at the molecular level.

“As we get to the bottom of a mystery that has perplexed the field for more than a decade, the story takes an unexpected twist that may hold clues to future antidepressants that would act through this counterintuitive resilience mechanism,” NIMH Director Thomas R. Insel, M.D., said in a statement about the Han paper.

Han’s group went on to show that using a clinically available drug (lamotrigine, which is used to treat depressive episodes in bipolar disorder) to increase the activity of the Ih channel in susceptible animals effectively made them resilient. “After five days of using this Ih potentiator in test mice, depression-related behaviors were all normalized,” Han says.

But there is a catch: before things got better, they got worse. Symptoms were more pronounced in the period up to the tipping point where the potassium channel counterbalance kicked in. From a clinical point of view, this could be troublesome. Depression already carries a risk of suicide, so pushing patients into a physiological state that may represent more intense depression could carry an unacceptable risk.

Han likens the phenomenon to a behavioral treatment called exposure therapy, which is used to treat Post-Traumatic Stress Disorder (PTSD). In exposure therapy, he says, “Patients are actually suffering more in the beginning, but eventually the brain adapts and you see treatment effects.” This mechanism may in fact explain why exposure therapy works, and certainly points to a possible mechanism of action for lamotrigine.

A New Direction for Drug Discovery in Psychiatry?
Either way, these findings inform drug-discovery efforts in psychiatric illness. The search for new medications that can effectively treat depression, PTSD, and other anxiety disorders has been a long, slow slog, but resilience research has the potential to take it in a new direction.

“Most efforts in drug development for depression in the last half century have focused on looking for ways to undo the bad effects of stress,” says Nestler. “But based on what we’ve learned, maybe a better way is to look for new ways to induce resilience.” Nestler and others are leading the charge to do just that, screening chemical libraries to identify candidate molecules and evaluate them first in the laboratory and then in animals to determine if human clinical trials are warranted. It’s a process that is not easy and will take a lot of time, he says.

In the meantime, behavioral therapies fill the gap where drugs cannot. In depression, cognitive behavioral therapy–a form of talk therapy performed by a psychotherapist–has been shown to be as effective as antidepressant medications in most patients. In PTSD, the gold standards of treatment are behavioral interventions: Prolonged Exposure Therapy, in which survivors repeatedly re-experience their traumatic event in safe environments, and Cognitive Processing Therapy, a talk therapy focused on challenging and modifying maladaptive beliefs related to the trauma. Kathleen Chard, Ph.D., a Veteran’s Administration researcher and professor of psychiatry and behavioral neuroscience at the University of Cincinnati, is leading a large, multisite VA-funded study to try to determine which of these therapies works best in which people, an outstanding question that has hampered best practices in treatment.

As a VA researcher and director of the Trauma Recovery Center at the Cincinnati VA Medical Center, Chard is interested in understanding which enlisted men and women are more susceptible to having a traumatic response to military service, and ensuring that those who are exposed to trauma get the right treatment to help prevent a downward cascade into chronic psychopathology. The “right” treatment might be different based on one’s genetic make-up and various interpersonal characteristics that seem to be linked to PTSD, such as temperament, the culture in which one is raised, and the environment that one is in after trauma occurs, she says.

“I think we have to be very cautious to adopt resiliency protocols that are actually proven to be effective in the area that we’re using them,” Chard says. “I don’t know that we can say that a resiliency protocol that’s good for high school students is good for police officers. We need to think about resilience as not being one size fits all.”