A single dose of the serotonin 2 receptor agonist psilocybin enhances behavioral flexibility by altering neural activity in the retrosplenial cortex. In a five-day trace fear learning and extinction assay using longitudinal single-cell calcium imaging in mice, psilocybin induced ensemble turnover between fear learning and extinction days, oppositely modulating activity in fear- and extinction-active neurons. Acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons predicted enhanced fear extinction. A computational model showed that acute inhibition of fear-active neurons by psilocybin suffices to explain its neural and behavioral effects days later, suggesting a new mechanism involving suppression of fear-active populations.
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.