The Medial Prefrontal Cortex Modulates Psychedelic-like Effects of Psilocin
Miyuan Zhang, Haiyan Zhai, Liu Yang, Haohong Li, Xiaohui Wang
ACS Pharmacology & Translational Science July 8, 2025 DOI: 10.1021/acsptsci.5c00324 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Intervention | Psilocin |
| Dose | picomolar dose |
| Measures | Head twitch response (HTR), c-Fos immunofluorescent labeling |
| Topics | Psilocybin |
| Keywords | Prefrontal cortex Consumer neuroscience |
| Citations | 1 |
| Key findings | The medial prefrontal cortex (mPFC) is a critical regulator of psilocin-induced psychedelic-like behavior, as demonstrated by c-Fos labeling and optogenetic manipulation in male mice. |
Abstract
Recent advancements in the study of psilocybin and its active metabolite psilocin have highlighted their unique psychedelic properties and potential therapeutic applications, particularly in the rapid and sustained treatment of depression. However, the potent acute psychedelic effects of psilocybin necessitate a deeper understanding of the neural mechanisms underlying its action. In this study, we investigated the psilocin-induced neural activity in male mice using c-Fos immunofluorescent labeling and identified brain regions associated with psychedelic-like activity. Among the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and dorsomedial striatum (DMS), only the mPFC was specifically associated with the head twitch response (HTR), a hallmark of psychedelic-like behavior. A picomolar dose of psilocin in the mPFC was sufficient to induce significant HTR, suggesting that c-Fos-positive neurons in this region modulate psychedelic-like activity. To validate this hypothesis, optogenetic activation of these neurons significantly increased spontaneous HTR in TRAP2 mice, whereas acute inhibition suppressed drug-induced HTR. These findings establish the mPFC as a critical regulator of psilocin-induced psychedelic-like activity and provide valuable insights for enhancing the clinical safety and therapeutic application of psychedelics.
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 35
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 30 more in the library