Prefrontal control of fear: more than just extinction

Abstract

Although fear research has largely focused on the amygdala, recent findings highlight cortical control of the amygdala in the service of fear regulation. In rodent models, it is becoming well established that the infralimbic (IL) prefrontal cortex plays a key role in extinction learning, and recent findings are uncovering molecular mechanisms involved in extinction-related plasticity. Furthermore, mounting evidence implicates the prelimbic (PL) prefrontal cortex in the production of fear responses. Both IL and PL integrate inputs from the amygdala, as well as other structures to gate the expression of fear via projections to inhibitory or excitatory circuits within the amygdala. We suggest that dual control of the amygdala by separate prefrontal modules increases the flexibility of an organism's response to danger cues.

Figure 1. Prefrontal control of fear expression and extinction

During fear expression (left) and extinction (right) of auditory fear conditioning, tone responses from the amygdala (amyg) get integrated by the prelimbic (PL) or infralimbic (IL) prefrontal cortex with converging information from diverse sources such as hippocampus (Hipp), brainstem monoamines (Bstm), mediodorsal thalamus (MD), and orbital prefrontal cortex (OFC) to determine whether or not to produce a fear response. Fear excitation involves PL projections back to basal amygdala (BA), whereas fear inhibition involves IL projections to amygdala intercalated cells (ITC). In turn, BA excites neurons in the medial division of the central nucleus of the amygdala (CeM) to produce fear responses, while ITCs inhibit these amygdala output neurons thereby inhibiting fear responses. Thus, the same conditioned stimulus (e.g. a tone) signals either high fear (red) or low fear (green) states in the appropriate circumstances.