The Medial PrefrontalCortex Modulates Psychedelic-likeEffects of Psilocin

Psilocin, the active metabolite of psilocybin, produces psychedelic effects by activating a specific region of the brain: the medial prefrontal cortex (mPFC). In male mice, a tiny dose of psilocin injected directly into the mPFC triggered a head twitch response, a behavioral marker of psychedelic activity. Artificially activating mPFC neurons with light increased these twitches, while inhibiting them suppressed drug-induced twitches. This identifies the mPFC as a key regulator of psilocin's psychedelic effects, offering a target for developing safer therapeutic applications of psychedelics for conditions like depression.

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.