Isehak, I. | Search bioRxiv

bioRxiv2026

The anterior insular cortex mediates higher-order threat learning and memory

Learning about potential threats is indispensable for survival, and its deficits underlie numerous neuropsychiatric disorders. Human brain imaging suggests the anterior insular cortex (AIC) as a key neural correlate of threat learning, yet its mechanistic role remains unclear. Leveraging multimodal systems neuroscience approaches, we demonstrate that AIC excitatory neurons, specifically layer 5 pyramidal neurons projecting to the basolateral amygdala, are essential for higher-order threat learning/memory. They are specifically required when a predictor is temporally separated from an aversive event or when the predictive information is embedded within a diffuse context. In contrast, the AIC is dispensable for elementary, temporally contiguous threat learning. Surprisingly, while the AIC promotes memory formation, it also constrains the level of fear expression during retrieval in a context-dependent manner. This bidirectional control is mediated by the recruitment of distinct AIC neuronal ensembles. Together, we identify a novel circuit mechanism for bidirectional regulation of higher-order threat learning/memory.

neuroscience↗

bioRxiv2021

The anterior insular cortex associates temporally discontiguous stimuli during threat learning

Learning about potential threats in the environment is indispensable for survival. Deficits in threat learning constitute a key dimension of multiple brain disorders, which include posttraumatic stress disorder and anxiety disorder. While human brain imaging studies have highlighted a reliable engagement of the anterior insular cortex (AIC) in threat learning, its precise role remains elusive partly due to the lack of animal studies that can address causality and mechanistic questions. Filling in this gap, the present mouse study proposes a novel AIC-mediated mechanism underlying the association of temporally discontiguous stimuli during threat learning. We identified that activity of AIC layer 5 (L5) pyramidal neurons is required for associating temporally discontiguous stimuli, specifically during a time interval between them. Notably, the AIC is not required for associating temporally contiguous stimuli during threat learning. The AIC not only sends the essential information, via its L5 pyramidal neurons, to the basolateral amygdala (BLA) during the time interval, but also receives from the BLA. We also identified a modulatory role of AIC dopamine D1 receptor (D1R)-mediated dopamine signaling in associating temporally discontiguous stimuli during the time interval.

neuroscience↗