TARGETING INSULO-FRONTAL PATHWAY TO REDUCE STRESS-EVOKED COGNITIVE RIGIDITY

Area of Science:

• Neuroscience
• Cognitive Science
• Behavioral Neuroscience

Background:

• The anterior insular cortex (aIC) is crucial for the salience network and cognitive flexibility.
• Cognitive rigidity is a hallmark of stress-related disorders, yet its neural underpinnings are not fully understood.
• The causal role of the aIC in cognitive rigidity remains unclear.

Purpose of the Study:

• To investigate the causal role of anterior insular cortex (aIC) projections to the medial prefrontal cortex (mPFC) in cognitive flexibility.
• To elucidate how stress impacts aIC function and cognitive flexibility.
• To identify the aIC→mPFC circuit as a potential therapeutic target for cognitive rigidity.

Main Methods:

• Attentional set-shifting tasks (AST) in mice.
• Optogenetic manipulation of aIC→mPFC projections.
• In vivo neural activity recording during cognitive tasks.
• Stress induction paradigms.

Main Results:

• aIC neurons projecting to the mPFC show heightened activity after incorrect trials, signaling salience.
• Optogenetic disruption of aIC→mPFC projections impairs adaptive decision-making and AST performance.
• Stress disrupts aIC activity's outcome-dependence and impairs set-shifting.
• Reinforcing aIC→mPFC activity after errors rescues cognitive flexibility in stressed mice.

Conclusions:

• The aIC→mPFC circuit is critical for linking trial outcomes to adaptive decision-making.
• This pathway plays a key role in maintaining cognitive flexibility.
• The aIC→mPFC circuit represents a promising therapeutic target for stress-induced cognitive rigidity.