Single-dose psilocybin promotes cell-type-specific changes of neurons in the orbitofrontal cortex
Ziran Huang, Xiaoyan Wei, Yihui Wang, Jin Tian, Jihui Dong, Bo Liang, Lin Lu, Wen Zhang
Neurotherapeutics 2026 DOI: 10.1016/j.neurot.2026.e00841 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male mice |
| Intervention | Psilocybin |
| Dose | a single dose |
| Duration | Long-term |
| Topics | Psilocybin |
| Keywords | Inhibitory postsynaptic potential Excitatory postsynaptic potential Hallucinogen Pyramidal cell Glutamate receptor Neurotransmission Synapse Orbitofrontal cortex |
| Key findings | Psilocybin induces long-term cell type-specific changes in the orbitofrontal cortex, primarily affecting layer 5 pyramidal neurons via 5-HT2A receptor activation, while sparing inhibitory neurons. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 3
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review International Journal of Molecular Sciences September 10, 2026
- 5-HT2A receptor activation is dispensable for psilocybin-induced fear extinction and neuroplasticity in mice. Chinese medical journal September 15, 2026
- Mapping excitatory synaptic plasticity evoked by single-dose psilocybin in mice
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