Single-dose psilocybin promotes cell-type-specific changes of neurons in the orbitofrontal cortex

A single dose of psilocybin, whose metabolite psilocin activates 5-HT2A receptors, induces long-term genetic and functional changes in the orbitofrontal cortex (OFC) of male mice. Layer 5 pyramidal neurons showed the most significant changes, including reduced expression of glutamate receptors and genes involved in excitatory synapse formation and maintenance, consistent with decreased excitatory synaptic transmission. Parvalbumin- and Somatostatin-positive inhibitory neurons showed minimal changes. Knocking down the 5-HT2A receptor in layer 5 pyramidal neurons, but not in Parvalbumin-positive inhibitory neurons, reduced psilocybin-induced functional changes and its antidepressant effect. These results reveal cell type-specific mechanisms of psilocybin and highlight brain region differences in psychedelic effects.

Study at a glance

Abstract

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-HT2A 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) of male mouse, a brain region vulnerable to psychological disorders such as depression. We found that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and the layer 5 pyramidal neurons showed the most significant changes. The layer 5 pyramidal neurons in the OFC showed reduced expressions of glutamate receptors and the gene expressions of multiple intercellular signaling pathways involved in the excitatory synapse formation and maintenance after psilocybin injection, which was consistent with the decreased excitatory synaptic transmission of these neurons. Meanwhile, both Parvalbumin- and Somatostatin-positive inhibitory neurons of the OFC showed meager changes after psilocybin injection. Furthermore, knockdown of 5-HT2A receptor in the layer 5 pyramidal neurons but not the Parvalbumin-positive inhibitory 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.