Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeuticsJan 31, 2026

Single dose of psilocybin causes specific changes in brain cells in the decision-making area

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 3, 2026

Abstract

A single dose of psilocybin induced long-term genetic and functional changes in neurons of the orbitofrontal cortex in male mice.

Layer 5 pyramidal neurons exhibited the most significant changes, including reduced expressions of glutamate receptors.
Gene expressions related to intercellular signaling pathways for excitatory synapse formation and maintenance were decreased in these neurons.
This reduction in gene expression was associated with decreased excitatory synaptic transmission in layer 5 pyramidal neurons.
Parvalbumin- and Somatostatin-positive inhibitory neurons displayed minimal changes after psilocybin treatment.
Knockdown of the 5-HT receptor in layer 5 pyramidal neurons diminished the functional changes and the anti-depressant effects of psilocybin.

Simplified

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-HTreceptor 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-HTreceptor 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. 2A2A

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Single dose of psilocybin causes specific changes in brain cells in the decision-making area

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