The Medial Prefrontal Cortex Modulates Psychedelic-like Effects of Psilocin

Psilocin, the active metabolite of psilocybin, induces psychedelic-like behavior in male mice by activating neurons in the medial prefrontal cortex (mPFC). Using c-Fos immunofluorescent labeling, the mPFC was the only brain region among several tested that was specifically associated with the head twitch response (HTR), a behavioral marker of psychedelic activity. A picomolar dose of psilocin directly into the mPFC triggered significant HTR. Optogenetic activation of these neurons increased spontaneous HTR, while acute inhibition suppressed drug-induced HTR. The findings establish the mPFC as a critical regulator of psilocin's psychedelic effects, offering insights for improving the clinical safety and therapeutic use of psychedelics.

Study at a glance

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.