Rescuing behavioral flexibility in a mouse model for OCD by enhancing reward-cue salience

Deficits in cognitive flexibility are a frequent symptom of obsessive-compulsive disorder (OCD) and have been hypothesized to underlie compulsive behavior. Sign- and goal-tracking behaviors are thought to be related to cognitive flexibility, yet have not been studied in this context. To investigate the relationship between sign- and goal-tracking behavior and cognitive flexibility, we tested SAPAP3 knockout mice (SAPAP3-/-) and wild-type littermate controls in a Pavlovian reversal-learning task with two conditioned stimuli, one predicting reward delivery and the other reward omission. SAPAP3-/- displayed a heterogenous reversal-learning performance: Half of the population failed to acquire the reversed cue-reward contingencies, whereas the other half reversed their approach behavior similar to control mice. Surprisingly, such behavioral inflexibility and compulsive-like grooming were unrelated, suggesting a non-causal relationship between these traits. Importantly, compromised reversal learning in impaired mice was associated with diminished sign-tracking behavior (and therefore presumably with an overreliance on goal-tracking behavior). Administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the first-line pharmacological OCD treatment, ameliorated both anxiety-like behavior and compulsive-like grooming, but did not improve behavioral flexibility in SAPAP3-/-. In contrast, enhancing reward-cue salience by altering conditioned stimuli brightness improved behavioral flexibility through augmenting sign-tracking behavior. These findings suggest that deficits in behavioral flexibility are associated with imbalanced sign- and goal-tracking behaviors in SAPAP3-/-, and enhancing reward-cue salience can rescue behavioral flexibility by restoring the balance. Thus, sign- and goal-tracking behavior might be an underexplored cognitive mechanism that could potentially be exploited to improve cognitive flexibility in OCD patients.