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Photo of Joshua A. Gordon, M.D., Ph.D.

Moving Stress Research Forward


Typical wooden dwelling in Ostrόw Mazowiecka at the time of World War I.
Typical wooden dwelling in Ostrόw Mazowiecka
at the time of World War I.

As a young child during World War I, my Grandmother lived in a one-story wooden house in Ostrόw Mazowiecka, a small town in northeastern Poland. Her father had left for the United States before the outbreak of the war, and her mother survived and supported her young family by washing laundry for the occupying German soldiers.

My family and I visited the town this summer to learn about our roots. We saw with our own eyes the few structures remaining from that period and learned about the history of the town’s Jewish residents, my ancestors, who had lived there since the middle ages. My Grandmother and her family joined her father in the U.S. after the end of World War I, and they were therefore spared the terrible fate of those Jews—some 10,000 of them—still living in Ostrόw Mazowiecka in 1939 when the occupation by Nazi Germany began.

Jewish residents corralled in the Ostrόw Mazowiecka town square by the Nazis in 1939.
Jewish residents corralled in the Ostrόw
Mazowiecka town square by the Nazis in 1939.

Like my Grandmother, survivors of these periods in history faced severe adversity. They faced difficulty every day providing food, shelter, and safety for themselves and their loved ones. They were often exposed to violence, and their freedom of movement, association, and communication was restricted. Equally challenging was the distress of not knowing what was to come next.

Research tells us that severe stresses like these, especially early in life, cause all kinds of adverse health outcomes, including increased risk for mental illnesses. After years of investments in stress research at NIMH and across the globe, we now know a lot about the biological substrates linking exposure to stressful events in the environment with changes in the brain that can lead to mental health problems. We know that stressors of all kinds, including both physical and psychological stressors, trigger the activation of stress hormones and brain pathways important for the regulation of both bodily functions and cognitive processes. For example, hormonal responses to stress enable the body to navigate threatening situations successfully and properly heal from significant injury, while brain responses enable humans and animals to learn from these stressors in order to avoid future threats. Although these pathways can be incredibly important for survival, they can also be maladaptive—especially with severe or chronic forms of stress—overwhelming both the brain and the rest of the body.

Both adaptive and maladaptive responses to stress result from a cascade of molecular, cellular, and neural-circuit level changes that have been, and continue to be, a subject of intense research efforts supported by NIMH and others. We know, for instance, that stress triggers activation of molecular processes that tag genes with so-called “epigenetic marks” that result in long-lasting changes in how the molecular machinery of those neurons is expressed. These marks can last for months, years, or perhaps even lifetimes. Changes in gene expression that result from these marks alter how neurons learn and respond to the environment, and even alter how the brain responds to future stresses. We know, at least in animals like mice and rats, that a range of different interventions can block or reverse many of these stress-induced processes, preventing some of the adverse behavioral responses to stress that we think might be relevant to human disorders like major depression and post-traumatic stress disorder (PTSD).

Despite this incredible knowledge base, we must admit that these investments have not resulted in substantial gains in the clinical realm. While this may seem a familiar refrain in mental illness research in general, the comparison between the tremendous gains in our knowledge of what stress does to the brain and the paucity of novel approaches to the prevention and treatment of stress-related disorders seemed particularly stark to me and others at NIMH. With this in mind, we set out over the past year to figure out how we might move the field more rapidly toward the translation of basic findings into clinical advances.

The first step was an in-depth look at the kinds of stress-related research NIMH has been funding. One of the first things we found was that our stress research portfolio has been making some important progress toward translation. For example, basic science researchers supported by NIMH have been moving toward more realistic models of stress. One way they have done this is by including chronic stressors in their models—we know that in humans, repeated and chronic stress plays a more pervasive role in various mental illnesses than do single, acute episodes of stress. More researchers are conducting studies examining stress in female animals, an important step forward because of the higher rates of stress-related disorders, like depression, in women. Currently-funded NIMH efforts have also been using more sophisticated and comprehensive analyses of molecular and brain circuit responses to stress. These studies have the promise of providing a more nuanced, multifaceted and holistic picture of the biology of the stress response than prior, single-pathway-at-a-time approaches. On the human research side, rigorous, well-designed longitudinal studies of responses to real-life stressors in children and adults promise to allow us to compare and contrast what happens in animal models with what happens in people.

The next step NIMH took to try to move this field forward was to set up and execute a series of webinars with a range of experts in the field to discuss the current status of stress-related research and what would be needed to enhance progress. This webinar series, in turn, spurred a series of internal discussions among NIMH program staff overseeing stress-related research.

There were several take-home points from these webinars and discussions. Chief among them was the notion that stress is a heterogeneous concept rather than a single entity. Our research, both basic and clinical, needs to take this heterogeneity into account, considering differences in both the nature and the developmental timing of the stressful exposure and the biological and behavioral responses to the exposure. We need to encourage investigators to integrate and synthesize results across studies using different stressors.

We also need a better understanding of adaptive vs. maladaptive responses and the features of resilient vs. vulnerable individuals. Approaches to studying multiple, interacting physiological systems and/or molecular pathways should also be encouraged. Ideally, such studies would lead to the development of translatable biomarkers that would facilitate the study of stress responses, resilience, and vulnerability across both human and animal studies. Such biomarkers would enable clinical scientists to make specific hypotheses about how likely it is that a given therapeutic or preventative measure would work in a specific person at risk due to stress.

The best stress research considers the complexity of both the stressor and the biological and psychological responses and works toward not simply understanding, but also translating, this knowledge for the betterment of the human condition. Though my Grandmother’s trials lay in the past, stress and its consequences are very much a part of our world today. Solutions for treatment and prevention of the mental health consequences of stress are greatly needed.