Psychedelics Relax Priors and Reshape Orbitofrontal Dynamics
C. Delgado-sallent, S. A. Ahmed, A. Khawaja-lopez, B. S. Lee, R.a. Senne, B. B. Scott, S. Ramirez
bioRxiv Preprint Server September 18, 2025 preprint DOI: 10.1101/2025.09.18.677110 via bioRxiv
Summary
Psychedelics like psilocybin and ketamine can slow decision-making times and enhance accuracy in mice by relaxing high-level cognitive priors, which allows sensory information to play a larger role. In a perceptual decision-making task, these substances led to increased decision thresholds and shifts towards sensory-engaged cognitive states. Brain mapping showed that psychedelics affect a decision-making network by modulating specific brain areas, indicating a reconfiguration of neural dynamics that supports more flexible decision-making.
Study at a glance
| Population | mice |
|---|---|
| Key finding | Acute administration of psilocybin or ketamine significantly slowed decision times and improved accuracy in a perceptual decision-making task. |
Abstract
Psychedelics such as psilocybin and ketamine are gaining attention as rapid-acting treatments for psychiatric disorders, yet the mechanisms by which they alter cognition remain unclear. A key hypothesis—the REBUS model—proposes that psychedelics relax high-level priors, allowing bottom-up sensory information to exert greater influence over perception and behavior. Here, we test this model in mice performing a free-response perceptual decision-making task that disambiguates prior-driven and sensory-driven decision strategies. Acute administration of psilocybin or ketamine significantly slowed decision times and improved accuracy. Behavioral modeling that combined drift diffusion and GLM-HMM frameworks revealed that these changes were mediated by increased decision thresholds and a marked shift into sensory-engaged cognitive states. Whole-brain c-Fos mapping identified a distributed decision-making network, with psychedelics selectively modulating cortical and subcortical nodes. Calcium imaging in the orbitofrontal cortex (OFC)—a key region for integrating priors and sensory inputs—revealed preserved decision-related selectivity under psychedelics, while exhibiting reduced neuronal correlations—population-level signatures of weakened top-down influence and relaxed priors. Together, these results provide circuit-level support for the REBUS model, showing that psychedelics reconfigure brain-wide and local dynamics to promote more deliberate, flexible, and sensory-driven decision policies.