bioRxiv : the preprint server for biologyJul 17, 2026

Psilocybin may improve thinking flexibility affected by abnormal error signals in decision-making areas

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 18, 2026

Abstract

Psilocybin ameliorated deficits in cognitive flexibility in mice with aberrant mesocortical signaling.

Cognitive inflexibility in mice was linked to specific circuit-level causes, notably aberrant mesocortical signaling.
Psilocybin was effective in reversing cognitive deficits associated with abnormal activity in the prefrontal cortex-mediodorsal thalamus circuit.
The drug reduced elevated activity in projection neurons during post-error exploration, both acutely and 24 hours later.
Lasting changes in neuron behavior were observed, with psilocybin enhancing thalamic input and reducing certain afterdepolarizations.
These cellular and circuit mechanisms may clarify the therapeutic specificity of psilocybin.

Simplified

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.