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

Jan 13, 2025bioRxiv : the preprint server for biology

Psilocybin's changing effects on gene activity in different brain cell types over time

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Abstract

Psilocybin induces time-dependent changes in gene expression in the medial frontal cortex, observed at various time points post-administration.

Gene expression changes were analyzed using single-nucleus RNA sequencing from male and female mice.
Excitatory neurons showed differentially expressed genes related to synaptic plasticity following psilocybin treatment.
GABAergic neurons exhibited gene changes associated with mitochondrial function and cellular metabolism after psilocybin administration.
Transcriptional responses to psilocybin were evident at early (1-2 hours) and late (72 hours) time points.
Ketamine also triggered transcriptional changes that correlated significantly with those induced by psilocybin.

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There is growing interest to investigate classic psychedelics as potential therapeutics for mental illnesses. Previous studies have demonstrated that one dose of psilocybin leads to persisting neural and behavioral changes. The durability of psilocybin's effects suggests that there are likely alterations of gene expression at the transcriptional level. In this study, we performed single-nucleus RNA sequencing of the dorsal medial frontal cortex of male and female mice. Samples were collected at 1, 2, 4, 24, or 72 hours after psilocybin or ketamine administration and from control animals. At baseline, major excitatory and GABAergic cell types selectively express particular serotonin receptor transcripts. The psilocybin-evoked differentially expressed genes in excitatory neurons were involved in synaptic plasticity, which were distinct from genes enriched in GABAergic neurons that contribute to mitochondrial function and cellular metabolism. The effect of psilocybin on gene expression was time-dependent, including an early phase at 1-2 hours followed by a late phase at 72 hours of transcriptional response after administration. Ketamine administration produced transcriptional changes that show a high degree of correlation to those induced by psilocybin. Collectively, the results reveal that psilocybin produces time-dependent and cell-type specific changes in gene expression in the medial frontal cortex, which may underpin the drug's long-term effects on neural circuits and behavior.

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

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