Posterior insular cortex is necessary for conditioned inhibition of fear

Abstract

Veridical detection of safety versus danger is critical to survival. Learned signals for safety inhibit fear, and so when presented, reduce fear responses produced by danger signals. This phenomenon is termed conditioned inhibition of fear. Here, we report that CS+/CS− fear discrimination conditioning over 5 days in rats leads the CS− to become a conditioned inhibitor of fear, as measured by the classic tests of conditioned inhibition: summation and retardation of subsequent fear acquisition. We then show that NMDA-receptor antagonist AP5 injected to posterior insular cortex (IC) before training completely prevented the acquisition of a conditioned fear inhibitor, while intra-AP5 to anterior and medial IC had no effect. To determine if the IC contributes to the recall of learned fear inhibition, injections of the GABAA agonist muscimol were made to posterior IC before a summation test. This resulted in fear inhibition per se, which obscured inference to the effect of IC inactivation with recall of the safety cue. Control experiments sought to determine if the role of the IC in conditioned inhibition learning could be reduced to simpler fear discrimination function, but fear discrimination and recall were unaffected by AP5 or muscmiol, respectively, in the posterior IC. These data implicate a role of posterior IC in the learning of conditioned fear inhibitors.

Cued fear memory generalization increases over time

“…Another interpretation is that Arc expression in the AIP and IL was actively "suppressed" over time, via inhibitory signaling. The IL has consistently been linked with suppressing conditioned fear responses, especially after extinction (Vidal-Gonzalez et al 2006), while the AIP has been associated with processing learned safety signals (conditioned inhibition of fear) (Foilb et al 2016). This leads to a model whereby over time, progressively increased suppression of IL and AIP output disinhibits amygdala circuits leading to exaggerated (generalized) CRs to novel tone stimuli.…”

Assaying Fear Memory Discrimination and Generalization: Methods and Concepts

“…Variations of the differential fear conditioning paradigm have been used to study "safety" learning and memory (Foilb, Flyer-Adams, Maier, & Christianson, 2016;Greiner, Müller, Norris, Ng, & Sangha, 2019;Müller, Brinkman, Sowinski, & Sangha, 2018;Sangha, Chadick, & Janak, 2013). While the various procedures for safety learning are outside of the scope of this methods article, there are several reviews on the topic (Christianson et al, 2012;Sangha et al, 2020).…”

The Posterior Insular Cortex is Necessary for the Consolidation of Tone Fear Conditioning

“…Muscimol (Sigma-Aldrich®), a selective GABA A agonist, was dissolved in sterile saline solution (0.9% NaCl). The dose of 0.5 µg/0.5 μ L was chosen based on previous studies that successfully inactivated the IC prior to aversive memory conditioning trainings (Berman et al, 2000;Casanova et al, 2016;Foilb et al, 2016;Koh & Bernstein, 2005;Rodríguez et al, 2020).…”