Valence-Driven Cognitive Flexibility: Neurochemical and Circuit-Level Insights from Animal Models and Their Relevance to Schizophrenia

Cognitive flexibility, the ability to adapt behavior to changing environmental demands, is a core deficit in schizophrenia (SZ), that predicts disease progression. This review synthesizes findings on the neural substates of cognitive flexibility by using a framework that distinguishes animal model tasks by their motivational valence: aversive versus appetitive. While human studies using tasks like the Wisconsin Card Sorting Test (WCST) reveal significant cognitive inflexibility in SZ, particularly in set-shifting, rodent models provide important mechanistic insights. Current literature suggests that aversive tasks, such as water mazes, and appetitive tasks, such as the Birrel-Brown discrimination task, engage distinct neural circuits, despite assessing supposedly similar cognitive processes. Aversive paradigms primarily rely on hippocampal-medial prefrontal cortex (mPFC) pathways, whereas appetitive tasks heavily involve orbitofrontal cortex (OFC)-striatal circuits, with significant modulation by dopamine and serotonin. Both valences seem to require an intact balance of glutamate and GABA transmission within prefrontal regions. This framework helps clarify inconsistencies in the literature and underscores how motivational context shapes the neural substrates of cognitive flexibility.