Conditioned fear associated phenotypes as robust, translational indices of trauma-, stressor-, and anxiety-related behaviors

Abstract

Post-traumatic stress disorder (PTSD) is a heterogeneous disorder that affects individuals exposed to trauma (e.g., combat, interpersonal violence, and natural disasters). It is characterized by hyperarousal, intrusive reminders of the trauma, avoidance of trauma-related cues, and negative cognition and mood. This heterogeneity indicates the presence of multiple neurobiological mechanisms underlying the development and maintenance of PTSD. Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis. Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study. Additionally, fear conditioning studies provide a translational platform to develop novel interventions. The current review highlights the versatility of fear conditioning paradigms, the implications for pharmacological and non-pharmacological treatments, the robustness of these paradigms to span an array of neuroscientific measures (e.g., genetic studies), and finally the need to understand the boundary conditions under which these paradigms are effective. Further understanding these paradigms will ultimately allow for optimization of fear conditioning paradigms, a necessary step towards the advancement of PTSD treatment methods.

Keywords: anxiety disorders; fear learning; startle reaction; translational medical research; traumatology.

Figure 1

Promising targets for the translational study of trauma-, stressor-, and anxiety-related fear behaviors: trauma-, stressor-, and anxiety-related disorders have been shown to have a significant degree of heritability and more recently, it has become increasingly clear that genetic contributions include complex gene × environment interactions. Understanding these complex relationships may allow for early interventions to enhance resiliency in certain individuals with a high risk of trauma. Fear-conditioning paradigms afford the study of intermediate phenotypes, which may enhance our ability to elucidate these complex interactions [see Ref. (36)]. The dysregulated fear learning commonly observed in anxious and traumatized populations can be modeled by fear-conditioning paradigms, which can provide a translational framework. Translational studies have shown that fearful memories are initially labile and are consolidated to a more permanent state, hours to days, after the initial event. Modeling the process of consolidation and reconsolidation with fear-conditioning techniques provides an avenue to study potential pharmacological and non-pharmacological interventions [e.g., Ref. (33, 37)]. Clinically, individuals with PTSD have been show to have alterations in stimulus generalization (16), fear inhibition (29), discrimination, and fear extinction (38). In addition to complementary psychophysiological methods (e.g., skin conductance, reaction time), fear-potentiated startle methods have proven to be quite useful for the study and/or manipulation of these targets to better understand and treat stressor-, trauma-, and anxiety-related disorders. Figure adapted from Jovanovic and Ressler (39).