Psychedelics Relax Priors and Reshape Orbitofrontal Dynamics
bioRxiv Preprint Server September 18, 2025 C. Delgado-Sallent, S. A. Ahmed, A. Khawaja-Lopez et al. preprint
Psychedelics like psilocybin and ketamine slow decision times and improve accuracy in mice performing a perceptual task. Behavioral modeling showed these changes stem from increased decision thresholds and a shift toward sensory-driven cognitive states. Whole-brain mapping revealed psychedelics selectively modulate a distributed decision-making network. Calcium imaging in the orbitofrontal cortex showed preserved decision-related selectivity but reduced neuronal correlations, indicating weakened top-down influence and relaxed prior expectations. These circuit-level findings support the REBUS model, suggesting psychedelics reconfigure brain dynamics to promote more deliberate, flexible, and sensory-driven decision policies.