Single-dose psilocybin promotes cell-type-specific changes of neurons in the orbitofrontal cortex
Neurotherapeutics – January 01, 2026
Source: OpenAlex
Summary
A single dose of the hallucinogen psilocybin, a key compound in Psychedelics and Drug Studies, profoundly alters brain biology. Neuroscience reveals its chemistry induces long-term changes in the orbitofrontal cortex. Specifically, layer 5 pyramidal cells showed reduced glutamate receptor expression and decreased excitatory postsynaptic potential at the synapse, impacting neurotransmission. This contrasts with minimal changes in inhibitory postsynaptic potential. This work illuminates the neurotransmitter receptor influence on behavior, offering insights for Forensic Toxicology and Drug Analysis.
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.