Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles.

A single dose of psilocybin enhances behavioral flexibility by altering neural activity in the retrosplenial cortex. Using longitudinal single-cell calcium imaging in mice during a 5-day trace fear learning and extinction assay, the study found that psilocybin suppressed fear-active neurons and recruited extinction-active neurons, a pattern that predicted improved fear extinction. A computational model showed that inhibiting simulated fear-active units modulated the recruitment of extinction-active units and behavioral variability in freezing, consistent with the experimental findings. These results suggest psilocybin promotes behavioral flexibility by reorganizing cortical ensembles in the retrosplenial cortex.

Study at a glance

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.