Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles.
Nature neuroscience – June 01, 2025
Source: PubMed
Summary
A single dose of psilocybin can help reduce fear responses by rewiring brain circuits, according to groundbreaking research using mouse models. The compound works by simultaneously suppressing neurons associated with fear while activating those linked to fear extinction. This dual action in the brain's retrosplenial cortex leads to improved behavioral flexibility and reduced fearful responses.
Abstract
The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay. We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction. In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.