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Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT 2A receptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT 2A receptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.
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Huang et al. (2024) studied this question.