Weight loss after obesity disrupts cognitive flexibility through sex-specific reinforcement learning strategies

Objective: Despite successful weight loss through various interventions, many individuals with a history of obesity regain weight frequently, yet the cognitive factors contributing to this relapse remain unclear. In this thesis, we test the hypothesis that persistent deficits in cognitive flexibility – specific maladaptive reinforcement learning strategies – undermine decision-making in the post-weight-loss state. Methods: Using a mouse model of diet-induced obesity followed by diet-induced weight loss, we investigated alterations in reward-guided decision-makings through 80:20 probabilistic reversal learning task and closed-economy progressive ratio task. Male and female mice underwent 8 weeks of high-fat diet (HFD)-induced obesity, followed by 6 weeks of chow diet-induced weight loss. Post-weight-loss mice and controls were tested on a modified probabilistic reversal learning (PRL) task to access cognitive flexibility and a closed-economy progressive ratio (PR) task to evaluate motivation. Reinforcement learning (RL) modeling was applied to dissociate latent decision-making parameters. Results: Both sexes achieved comparable weight loss, but post-weight loss mice exhibited persistent deficits in PRL performance: male showed reduced efficiency during late phase reversal learning (p < 0.001), while females showed early-phase impairments (p<0.05) but recovered later. RL modeling revealed reduced learning rate in post-weight-loss mice, indicating impaired value updating despite intact motivation (no PR task differences). Females compensated for early deficits through dynamic adjustment, whereas males remained inflexible, suggesting sex-specific strategies. Conclusions: These findings demonstrate that prior obesity induced long-lasting, sex-divergent cognitive inflexibility, characterized by maladaptive reinforcement learning, which may explain vulnerability to relapse. This demonstrates the need for targeted interventions addressing post-weight-loss cognitive barriers to improve maintenance outcomes.