The S1-insula Circuit Differentially Modulates Alcohol Drinking and Aversive Behavior in Mice.

Sensory processing assigns salience to environmental and internal stimuli, shaping behavior through learned associations. In alcohol use disorder (AUD), sensory cue processing is dysregulated, driving problematic drinking patterns and hyperkatifeia in abstinence. While visual, olfactory, and taste cues are known to influence AUD progression, the neurocircuit mechanisms that regulate sensory information in addiction remain poorly understood. The primary somatosensory cortex (S1) encodes tactile, thermal, proprioceptive, and nociceptive inputs and projects to higher-order regions involved in motor and emotional processing. One such target is the insula, a hub for interoceptive integration and affective regulation. We previously identified that insula neurons receiving S1 projections in turn extend into the extended amygdala, implicating this projection in emotional processing. Here, we map S1-insula collateralizations in downstream motor and sensory processing regions, suggesting the unique role of this circuit in AUD-related behavior. Using chemogenetics, fiber photometry, and two complementary models of AUD-binge-like drinking and chronic drinking with forced abstinence-we demonstrate that the S1-insula circuit is selectively recruited during ethanol drinking and aversive behaviors in female mice. Chronic ethanol exposure disrupts this circuit's engagement, suggesting a maladaptive shift in sensory-affective integration. Notably, S1-insula neurons show both immediate and delayed activity increases in response to an ethanol lick, indicating temporally distinct roles. These findings reveal a unique cortico-cortical mechanism by which somatosensory signaling modulates external cue reactivity and internal affective states in AUD. This work underscores the role of sensory networks in addiction and identifies a potential circuit-level target for future diagnostic and therapeutic strategies.