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At the neural level, HDAC5 overexpression in DS elevated and reduced the number of cells in DLS that increased firing to stimuli and reward, respectively, and shifted encoding toward cues that predicted more immediate reward. These results suggest that the HDAC5 overexpression in DS contributes to inflexible decision-making, demonstrating a role of histone modifying enzymes in complex cognitive function.SIGNIFICANCE STATEMENT Histone deacetylases (HDACs) are important for learning and habit formation. Here, we expanded on these functions