BACKGROUND: 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. The primary motor cortex (MOp) provides substantial input to the mIC; however, the extent of the input remains unknown.

METHODS: We used anterograde and retrograde tracing, whole-cell patch-clamp electrophysiology, fiber photometry, and chemogenetics to investigate MOp innervation of the mIC (MOp) and identified somatostatin interneurons (SST-INs) as a preferential target. We performed a series of studies to determine how these cells influence BNST-projecting mIC (mIC), participate in stress responses, and regulate affective behavior in mice.

RESULTS: MOp afferents form excitatory synapses onto mIC SST-INs, which in turn inhibit mIC projection neurons, revealing a feed-forward inhibitory circuit. We previously found that physical active coping activity during restraint stress was associated with MOp 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 5 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.

CONCLUSIONS: 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 motor-related activity to stress regulation. Signals from motor areas activate specific inhibitory cells in the insular cortex. Activation of these inhibitory cells reduces anxiety-like behavior in mice. These cells remain active across repeated stress, suggesting a protective role. These findings help explain how motor-related behaviors, such as physical activity, may support emotional resilience and reduce negative feelings during stress.