Insular somatostatin interneurons are targeted by motor cortex efferents and modulate affective states.

Stress-related psychiatric disorders often involve disrupted corticolimbic communication. The mid-insular cortex (mIC) negatively regulates affective behavior through projections to the bed nucleus of the stria terminalis (BNST), however the architecture of synaptic governance of this path is not clear. Primary motor cortex (MOp) provides substantial input to mIC; however, the extent of the input remains unknown. We used anterograde and retrograde tracing, whole-cell patch clamp electrophysiology, fiber photometry, and chemogenetics to investigate MOp innervation of mIC (MOp IC ), and identified somatostatin interneurons (SST-INs) as a preferential target. We performed a series of studies to determine how these cells influence mIC BNST-projecting neurons (mIC BNST ), participate in stress responses and regulate affective behavior in mice. MOp afferents form excitatory synapses onto mIC SST-INs, which in turn inhibit mICBNST projection neurons, revealing a feed-forward inhibitory circuit. We previously found that physical active coping activity during restraint stress is associated with MOp IC activity. Here we extend this by finding that mIC SST-INs are also activated during these events. Notably, mIC SST-IN activation remains stable across five days of repeated restraint, suggesting resistance to stress habituation. Finally, chemogenetic stimulation of mIC SST-INs reduced negative affective-like behavior across several tasks, indicating a role in regulating affective behavior. Our findings uncover a novel motor afferent-driven inhibitory circuit within the mIC that preferentially targets SST-INs that regulate affective behavior, providing insight into potential targets for therapeutic intervention in stress-related affective disorders. This issue uncovers a brain circuit linking movement-related activity to stress regulation. Signals from motor areas activate specific inhibitory cells in the insular cortex. Activation of these inhibitory cells reduce anxiety-like behavior in mice. These cells remain active across repeated stress, suggesting a protective role. The findings help explain how motor-related behaviors, such as physical activity, may support emotional resilience and reduce negative feelings during stress.