Psilocybin selectively rescues cognitive flexibility impairments caused by aberrant prefrontal error signaling

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.

Study at a glance

Abstract

Psychedelic drugs show remarkable potential for treating psychiatric disorders, but the mechanisms underlying their therapeutic effects remain relatively unknown. Here, we demonstrate that psilocybin can powerfully ameliorate deficits in cognitive flexibility, but this effect depends on the specific circuit-level cause of those deficits. Using optogenetic models of cognitive inflexibility in mice, psilocybin rescued deficits caused by aberrant mesocortical signaling but failed to rescue deficits arising from disrupted interhemispheric gamma synchrony. Aberrant mesocortical signaling drove abnormally elevated activity in prefrontal cortex-mediodorsal thalamus (PFC-MD) projection neurons during post-error exploration, and psilocybin attenuated this pathological activity both acutely and 24 hours later. Patch-clamp electrophysiology revealed that psilocybin induces lasting plasticity in PFC-MD neurons, potentiating thalamic inputs while suppressing dopamine- and NMDA-receptor-dependent afterdepolarizations that could otherwise sustain aberrant post-error signaling. These findings reveal cellular and circuit mechanisms that could explain psilocybin's therapeutic specificity and establish a precision medicine framework approach for psychedelic treatment.