Psilocybin selectively rescues cognitive flexibility impairments caused by aberrant prefrontal error signaling
bioRxiv July 9, 2026 Christine Liu, Ellie M. Ho, Alexander S. Enos et al.
Psilocybin can improve cognitive flexibility, but only when the impairment stems from a specific brain-circuit problem. In mice, psilocybin reversed deficits caused by abnormal signaling between the prefrontal cortex and the mediodorsal thalamus, but it did not help deficits caused by disrupted communication between brain hemispheres. The drug reduced overactivity in prefrontal-thalamic neurons during post-error exploration, an effect that lasted at least 24 hours. It also triggered lasting changes in those neurons, strengthening inputs from the thalamus while dampening afterdepolarizations that sustain aberrant signaling. These results suggest psilocybin's therapeutic effects are circuit-specific and point toward a precision-medicine approach for psychedelic treatments.