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
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
“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’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
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