The Medial PrefrontalCortex Modulates Psychedelic-likeEffects of Psilocin
OPAL (Open@LaTrobe) (La Trobe University) – July 08, 2025
Source: OpenAlex
Summary
A picomolar dose of psilocin in the medial prefrontal cortex (mPFC) can induce psychedelic-like behavior. Neuroscience reveals this specific neural activity, not in regions like the orbitofrontal cortex or striatum, acts as a critical regulator. Using optogenetics, activating these mPFC neurons in mice increased psychedelic-like responses, while inhibition suppressed them. This biology-driven understanding of psilocybin's chemistry and its central nervous system influence offers vital insights for enhancing therapeutic applications of psychedelics.
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.