Single-nucleus transcriptomics reveals time-dependent and cell-type-specific effects of psilocybin on gene expression

Area of Science:

• Neuroscience
• Genomics
• Pharmacology

Background:

• Classic psychedelics, like psilocybin, show therapeutic potential for mental illnesses.
• Psilocybin administration induces lasting neural and behavioral changes, suggesting transcriptional alterations.
• Understanding the molecular mechanisms of psychedelics is crucial for therapeutic development.

Purpose of the Study:

• To investigate the time-dependent and cell-type specific gene expression changes induced by psilocybin in the mouse brain.
• To compare the transcriptional effects of psilocybin with ketamine.

Main Methods:

• Single-nucleus RNA sequencing was performed on the dorsal medial frontal cortex of mice.
• Samples were collected at various time points (1-72 hours) after psilocybin or ketamine administration.
• Differential gene expression analysis was conducted across different cell types.

Main Results:

• Psilocybin altered gene expression in excitatory neurons (synaptic plasticity) and GABAergic neurons (mitochondrial function).
• Transcriptional responses to psilocybin were time-dependent, with early (1-2 hours) and late (72 hours) phases.
• Ketamine induced transcriptional changes highly correlated with those of psilocybin.

Conclusions:

• Psilocybin induces distinct, time-dependent, and cell-type specific gene expression changes in the medial frontal cortex.
• These molecular alterations may underlie the long-term effects of psilocybin on neural circuits and behavior.
• The shared transcriptional pathways between psilocybin and ketamine suggest common mechanisms of action.