Know thy SEFL: Fear sensitization and its relevance to stressor-related disorders

Abstract

Extreme stress can cause long-lasting changes in affective behavior manifesting in conditions such as post-traumatic stress disorder (PTSD). Understanding the biological mechanisms that govern trauma-induced behavioral dysregulation requires reliable and rigorous pre-clinical models that recapitulate multiple facets of this complex disease. For decades, Pavlovian fear conditioning has been a dominant paradigm for studying the effects of trauma through an associative learning framework. However, severe stress also causes long-lasting nonassociative fear sensitization, which is often overlooked in Pavlovian fear conditioning studies. This paper synthesizes recent research on the stress-enhanced fear learning (SEFL) paradigm, a valuable rodent model that can dissociate associative and nonassociative effects of stress. We discuss evidence that the SEFL paradigm produces nonassociative fear sensitization that is distinguishable from Pavlovian fear conditioning. We also discuss key biological variables, such as age and sex, neural circuit mechanisms, and crucial gaps in knowledge. We argue that nonassociative fear sensitization deserves more attention within current PTSD models and that SEFL provides a valuable complement to Pavlovian conditioning research on trauma-related pathology.

Keywords: Associative; Fear; Fear sensitization; Nonassociative Learning; PTSD; Stress.

Figure 1.

General procedures and outcomes for stress enhancement of fear learning (SEFL). Stress-induction: mice or rats receive repeated or no footshocks in context A. Single-trial fear conditioning: the next day (or weeks later) all subjects, receive a single footshock after a few minutes in a novel context B, and 24 hrs later are returned to context B to assess freezing. As depicted in the simulated bar graph, the group previously exposed to stress exhibits greater freezing than the non-stressed group in context B.