Know safety, no fear

Abstract

Every day we are bombarded by stimuli that must be assessed for their potential for harm or benefit. Once a stimulus is learned to predict harm, it can elicit fear responses. Such learning can last a lifetime but is not always beneficial for an organism. For an organism to thrive in its environment, it must know when to engage in defensive, avoidance behaviors and when to engage in non-defensive, approach behaviors. Fear should be suppressed in situations that are not dangerous: when a novel, innocuous stimulus resembles a feared stimulus, when a feared stimulus no longer predicts harm, or when there is an option to avoid harm. A cardinal feature of anxiety disorders is the inability to suppress fear adaptively. In PTSD, for instance, learned fear is expressed inappropriately in safe situations and is resistant to extinction. In this review, we discuss mechanisms of suppressing fear responses during stimulus discrimination, fear extinction, and active avoidance, focusing on the well-studied tripartite circuit consisting of the amygdala, medial prefrontal cortex and hippocampus.

Keywords: Amygdala; Avoidance; Cortex; Discrimination; Extinction; Fear; Generalization; Hippocampus; Safety.

Figure 1.. Measuring behavioral responses of fear discrimination, generalization and safety.

A. Generalization levels can be tested after fear conditioning to a CS+ (orange) with an array of novel tone stimuli (a-e; black) of increasing similarity to the CS+. B. Generalization levels can also be assessed following fear conditioning to a cue or context predicting shock (CS+, CtxA+) and a separate cue or context predicting no shock (CS−, CtxB−); individuals show strong discrimination when the conditioned response is different (left graph), and strong generalization when the conditioned response is similar across cues/contexts (right graph). C. Schematic depicting procedural differences in experiments designed to investigate safety. In a within-subjects design (left) each subject is trained to both CS+ and CS− associations. In a between-subjects design (right) each subject is either trained to a CS+ or CS− association.

Figure 2:. Proposed fear suppression circuitry engaged during an explicit safety cue, an extinguished fear cue, or avoidance signal.

Blue arrows indicate increased activity in projections associated with increased acquisition/consolidation of fear suppression. Green arrows indicate increased activity in projections onto local inhibitory interneurons associated with increased expression of learned fear suppression. Red arrows indicate projections where increased activity is associated with a loss of fear suppression.