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

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.