Psilocybin selectively rescues cognitive flexibility impairments caused by aberrant prefrontal error signaling
Christine Liu, Ellie M. Ho, Alexander S. Enos, Urte Beatrice Baublyte, Isabel M. Luna, Alexander R. Kosche, Vikaas S. Sohal
bioRxiv July 9, 2026 preprint DOI: 10.64898/2026.07.05.736652 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Topics | Psilocybin |
| Key findings | Psilocybin rescues cognitive flexibility deficits caused by aberrant mesocortical signaling but not those from disrupted interhemispheric gamma synchrony, by attenuating pathological activity in prefrontal-mediodorsal thalamus neurons and inducing lasting plasticity. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cites 25
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences Journal of Psychopharmacology August 31, 2016
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
and 20 more in the library