Targeting insulo-frontal pathway to reduce stress-evoked cognitive rigidity

The anterior insular cortex (aIC), a central hub of the salience network, is engaged by cognitive flexibility tasks^1,2; it is also implicated in stress-related mental disorders^3-5, where cognitive rigidity is a common but poorly treated symptom¹. While the insular cortex's roles in interoception and emotional regulation are extensively studied^6-10, its causal contribution to cognitive rigidity remains unclear. Using attentional set-shifting tasks (AST) in mice, we identify aIC neurons projecting to the medial prefrontal cortex (mPFC) as key regulators of adaptive decision-making. These neurons show heightened activity following incorrect-but not correct-trials. This elevated activity persists into subsequent trials, providing a salience signal that enhances mPFC outcome-dependent updating and promotes convergence of neural activity patterns across trials. Optogenetic manipulation of aIC→mPFC projections during the pre-decision phase disrupts mPFC updating and impairs AST performance. Moreover, stress disrupts the outcome-dependence of aIC activity and impairs set-shifting. Crucially, selectively reinforcing aIC→mPFC activity after incorrect trials via optogenetics enhances mPFC updating, improves neural activity convergence across trials, and restores cognitive flexibility in stressed mice. These findings reveal a previously unrecognized role of the aIC→mPFC circuit in linking trial outcomes to adaptive decision-making and identify this pathway as a promising target for treating stress-induced cognitive rigidity.