A top-down insular cortex circuit crucial for non-nociceptive fear learning

Understanding how threats in environments drive fear memory formation is crucial to understanding how organisms adapt to changing environments and treat threat-related disorders such as PTSD. Despite decades of pioneering work using the Pavlovian conditioning model, our understanding has been limited because only one type (an electric shock) among diverse threats has been exclusively used. We developed a threat conditioning paradigm by utilizing a looming visual threat as an unconditioned stimulus (US) in mice and identified a distinct threat conditioning circuit. Parabrachial CGRP neurons were required for conditioning and memory retrieval. Their upstream neurons in the posterior insular cortex (pIC) responded to looming stimuli and projections of these neurons to the parabrachial nucleus induced aversive affective states and drove conditioning. But the pIC to PBN pathway was dispensable for foot-shock conditioning. Our findings provide insights into how a simple pattern of non-nociceptive visual stimuli can induce aversive states and drive fear memory formation.