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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, 2011-

Schizophrenia*/physiopathology ; Schizophrenia*/metabolism ; Cognition*/physiology; Animals ; Humans ; Disease Models, Animal ; Prefrontal Cortex/metabolism ; Prefrontal Cortex/physiopathology ; Motivation ; Dopamine/metabolism ; Cognitive Flexibility

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. The 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.

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Keywords: animal models; attentional set shifting; cognitive deficits; extra-dimensional set shifting; intra-dimensional set shifting; reversal learning

VTD58H1Z2X (Dopamine)

Date Created: 20250828 Date Completed: 20250828 Latest Revision: 20250831

20250903

PMC12384553

10.3390/biom15081154

40867599