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

Zuo, Yi1; Ma, Shaorong1; Wang, Kuan Hong2

Published Jul 09, 2026 on Dryad. https://doi.org/10.5061/dryad.2rbnzs857

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Abstract

Cognitive rigidity often follows chronic stress and is prevalent in stress-related psychiatric disorders, yet the underlying neural circuit mechanisms remain unclear. Using attentional set-shifting tasks (AST) in mice, we identified projection from the anterior insular cortex to the medial prefrontal cortex (aIC→mPFC) as key regulators of adaptive decision-making. The aIC→mPFC 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, chronic stress disrupts the outcome-dependence of aIC activity and impairs cognitive flexibility. 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 revealed a previously unrecognized role of the aIC→mPFC circuit in linking trial outcomes to adaptive decision-making and identified this pathway as a promising target for treating stress-induced cognitive rigidity.