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

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.

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Abstract

Abstract The serotonin 2 receptor (5HT2R) agonist psilocybin displays rapid and persistent therapeutic efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. A single dose of psilocybin induced ensemble turnover between fear learning and extinction days while oppositely modulating activity in fearand extinctionactive neurons. The acute suppression of fear-active neurons and delayed recruitment of extinction-active neurons were predictive of psilocybin-enhanced fear extinction. A computational model revealed that acute inhibition of fear-active neurons by psilocybin is sufficient to explain its neural and behavioral effects days later. These results align with our hypothesis and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.