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Assessment of Stress Effects on Cognitive Flexibility using an Operant Strategy Shifting Paradigm

Assessment of Stress Effects on Cognitive Flexibility using an Operant Strategy Shifting Paradigm

Published on: May 4, 2020

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

Shaorong Ma¹, Kuan Hong Wang², Yi Zuo³

¹Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA, USA.

Nature Communications

|April 27, 2026

Summary

Chronic stress causes cognitive rigidity, impairing decision-making. Researchers found the anterior insular cortex to medial prefrontal cortex (aIC→mPFC) circuit is crucial for adaptive decisions and can be targeted to restore flexibility.

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Area of Science:

Neuroscience
Behavioral Neuroscience
Psychiatry

Background:

Cognitive rigidity is a hallmark of chronic stress and stress-related psychiatric disorders.
The neural circuits underlying stress-induced cognitive inflexibility are not well understood.
Adaptive decision-making relies on updating based on outcomes.

Purpose of the Study:

To investigate the neural circuit mechanisms of cognitive rigidity following chronic stress.
To identify the role of the anterior insular cortex to medial prefrontal cortex (aIC→mPFC) pathway in adaptive decision-making and cognitive flexibility.
To explore therapeutic potential of targeting the aIC→mPFC circuit for stress-induced cognitive impairment.

Main Methods:

Utilized attentional set-shifting tasks (AST) in mice to assess cognitive flexibility.
Employed optogenetics to manipulate aIC→mPFC neuronal activity.
Recorded neural activity in the aIC→mPFC circuit during cognitive tasks.
Induced chronic stress in mice to model stress-related psychiatric conditions.

Main Results:

The aIC→mPFC pathway was identified as critical for adaptive decision-making.
Heightened aIC→mPFC activity after incorrect trials enhanced medial prefrontal cortex (mPFC) updating and neural activity convergence.
Optogenetic disruption of aIC→mPFC projections impaired cognitive flexibility.
Chronic stress disrupted outcome-dependent aIC activity and cognitive flexibility.
Reinforcing aIC→mPFC activity after incorrect trials restored cognitive flexibility in stressed mice.

Conclusions:

The aIC→mPFC circuit plays a key role in linking trial outcomes to adaptive decision-making.
This pathway is disrupted by chronic stress, contributing to cognitive rigidity.
Targeting the aIC→mPFC circuit offers a potential therapeutic strategy for stress-induced cognitive inflexibility.