Finding translation in stress research

Abstract

In our ongoing efforts to advance understanding of human diseases, translational research across rodents and humans on stress-related mental disorders stands out as a field that is producing discoveries that illuminate mechanisms of risk and pathophysiology at a brisk rate. Here we offer a Perspective on how a productive translational research dialog between preclinical models and clinical studies of these disorders is being powered by an ever-developing appreciation of the shared neural circuits and genetic architecture that moderate the response to stress across species. Working from these deep foundations, we discuss the approaches, both traditional and innovative, that have the potential to deliver a new generation of risk biomarkers and therapeutic strategies for stress-related disorders.

Figure 1

A brief timeline of some major milestones - past, present and future - related to the observation, classification, and scientific study of stress and stress-related disorders.

Figure 2

Pre-existing variability in a highly conserved neural circuitry for stress responsiveness predicts vulnerability for stress-related dysfunction. Top Panel: Individual differences in human amygdala reactivity to threat-related facial expressions predict psychological vulnerability to future stress. Participants with relatively greater amygdala reactivity (red) are more likely to experience symptoms of depression and anxiety if they encounter stressors up to four years later. Bottom Panel: Individual differences in the volume of the basolateral amygdala in mice predict sensitivity to fear conditioning. Mice with a relatively smaller basolateral amygdala (red) are more likely to express persistent, extinction-resistant conditioned fear responses.

Figure 3

Translational research has revealed convergent processes at multiple levels of analysis associated with the stress-related disorders.