Interoceptive Insular Cortex Mediates Both Innate Fear and Contextual Threat Conditioning to Predator Odor

Abstract

The insular cortex (IC), among other brain regions, becomes active when humans experience fear or anxiety. However, few experimental studies in rats have implicated the IC in threat responses. We have recently reported that inactivation of the primary interoceptive cortex (pIC) during pre-training, or the intra-pIC blockade of protein synthesis immediately after training, impaired the consolidation of auditory fear conditioning. The present study was designed to investigate the role of the pIC in innate and learned defensive responses to predator odor. Freezing behavior was elicited by single or repetitive exposures to a collar that had been worn by a domestic cat. Sessions were video-recorded and later scored by video observation. We found that muscimol inactivation of the pIC reduced the expression of freezing reaction in response to a single or repeated exposure to cat odor. We also found that pIC inactivation with muscimol impaired conditioning of fear to the context in which rats were exposed to cat odor. Furthermore, neosaxitoxin inactivation of the pIC resulted in a prolonged and robust reduction in freezing response in subsequent re-exposures to cat odor. In addition, freezing behavior significantly correlated with the neural activity of the IC. The present results suggest that the IC is involved in the expression of both innate and learned fear responses to predator odor.

The effects of predator odor (TMT) exposure and mGlu3NAM pretreatment on lasting behavioral and molecular adaptations in the insular cortex and BNST

“…Alternatively, these data could reflect differences in the composition of glutamate receptors that potentially result in functional differences. Because the insular cortex is involved in negative affect, anxiety, fear memories and threat conditioning [31, 34, 35, 41, 63], and NMDA receptor adaptations are involved in synaptic plasticity in the insular cortex [64], these adaptations could in part underlie the hypervigilance phenotype observed in the context re-exposure test.…”

“…The insular cortexr cortex and BNST form reciprocal projections [71, 72] and both regions contribute to affective behavioral measures in rodents [34, 35, 73] and humans [31]. Recent studies have shown that insular cortex/BNST circuitry are involved in negative affective measures associated with alcohol withdrawal in rodents [41].…”

“…In animal models, the insular cortex and the bed nucleus of the stria terminalis (BNST) both play an important role in stress responses [30, 31]. The insular cortex is commonly associated with the integration of sensory and interoceptive processing [32, 33], which is highly sensitive to stress and anxiety in preclinical models [34, 35] and implicated in the etiology of neuropsychiatric disorders [36]. For example, inactivation of the anterior insular cortex produced anxiogenic-like effects, whereas activation of the insular cortex produced anxiolytic-like effects as assessed by the elevated plus maze test [34].…”

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).…”

An Inescapable Cat Odor Exposure Protocol for Studying Innate and Contextual Threat Conditioning in Rats

“…Data are expressed as means + SEM. *p < 0.05.This figure has been modified from8 . Abbreviations: pIC = primary interoceptive cortex; Sal-Sal = saline injected on day…”