Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles.
Sophie A. Rogers, Elizabeth A. Heller, Gregory Corder
Nature Neuroscience June 1, 2025 DOI: 10.1038/s41593-025-01964-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Longitudinal Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | a single dose |
| Duration | 5-day trace fear learning and extinction assay |
| Topics | Psilocybin |
| Keywords | Psychedelics Fear-response Brain-plasticity Behavioral-science |
| Citations | 11 |
| Post-publication review | 1 comment on PubPeer (opens in new tab) · last active August 2025 |
| Key findings | Psilocybin enhances fear extinction by suppressing fear-active neurons and recruiting extinction-active neurons in the retrosplenial cortex. |
Abstract
The psychedelic drug psilocybin demonstrates rapid and long-lasting efficacy across neuropsychiatric disorders that are characterized by behavioral inflexibility. However, its impact on the neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test whether psilocybin enhances behavioral flexibility by altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the mouse retrosplenial cortex across a 5-day trace fear learning and extinction assay. We found that a single dose of psilocybin altered cortical ensemble turnover and oppositely modulated fear- and extinction-active neurons. Suppression of fear-active neurons and recruitment of extinction-active neurons predicted psilocybin-enhanced fear extinction. In a computational model of this microcircuit, inhibition of simulated fear-active units modulated recruitment of extinction-active units and behavioral variability in freezing, aligning with experimental results. These results suggest that psilocybin enhances behavioral flexibility by recruiting new neuronal populations and suppressing fear-active populations in the retrosplenial cortex.
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
Cited by 8
- Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks Cell December 5, 2025
- Psilocybin Enhances Cued Fear Extinction and Extinction Recall in Stress-Naïve, Acutely Stressed, and Chronically Stressed Mice ACS Pharmacology & Translational Science September 11, 2025
- Short- and long-term modulation of rat prefrontal cortical activity following single doses of psilocybin Molecular Psychiatry August 26, 2025
- Acute psilocybin or ethocybin leads to a sustained increase in Pavlovian aversion memory in male mice Frontiers in Pharmacology September 22, 2026
- Investigational drugs in PTSD. Neuropsychopharmacology June 1, 2026
and 3 more in the library
Cites 48
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
- Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences April 11, 2016
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 43 more in the library