Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

Abstract

Background: Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking. Methods: We examined the acute effects of a single administration of psilocybin (0.5–20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting. Results: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses. Conclusion: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…A recent study reported that psilocybin modulates neurotrophic-related gene expression in the PFC and hippocampus, with a preferential effect on the PFC, but inducing changes which are also appreciable in the hippocampus (Jefsen et al, 2020). More specifically, in the PFC psilocybin increased the expression of CEBPB, c-Fos, dual specificity protein phosphatase 1 (Dusp1), transcription factor jun-b, NF-kappa-b inhibitor-a (Ikba), nuclear receptor subfamily 4 group A member 1, while the serine/threonine-protein kinase 1 (Sgk1), protein fosB, protein S100-A10, and postsynaptic density protein 95 were increased only response to some doses of psilocybin.…”

“…More specifically, in the PFC psilocybin increased the expression of CEBPB, c-Fos, dual specificity protein phosphatase 1 (Dusp1), transcription factor jun-b, NF-kappa-b inhibitor-a (Ikba), nuclear receptor subfamily 4 group A member 1, while the serine/threonine-protein kinase 1 (Sgk1), protein fosB, protein S100-A10, and postsynaptic density protein 95 were increased only response to some doses of psilocybin. Dual specificity protein kinase (CLK1) was dose dependently decreased in response to psilocybin (Jefsen et al, 2020). In the hippocampus, Dusp1, Ikba, and Sgk1 transcripts were similarly increased by acute psilocybin and Clk1 expression was strongly decreased (Jefsen et al, 2020).…”

“…Dual specificity protein kinase (CLK1) was dose dependently decreased in response to psilocybin (Jefsen et al, 2020). In the hippocampus, Dusp1, Ikba, and Sgk1 transcripts were similarly increased by acute psilocybin and Clk1 expression was strongly decreased (Jefsen et al, 2020). Psilocybin affects hippocampal neurogenesis in a biphasic fashion (Catlow et al, 2013).…”

LSD induces increased signalling entropy in rats’ prefrontal cortex

“…Nevertheless, molecular mechanisms underlying acute changes in brain activity and lasting psychological effects have been less investigated. Neuroplasticityrelated genes and immediate early genes have been reported to be over-expressed upon psychedelics' administration in rodent models, especially in areas with dense 5-HT2A receptor expression like the prefrontal cortex (Benekareddy et al, 2013;González-Maeso et al, 2003, 2007Jefsen et al, 2020;C. D. Nichols et al, 2003).…”

Psychedelics: Old drugs, new trips

“…Similar to previous studies, DMT suppressed 8–12 Hz (alpha) oscillations, whilst changes in the gamma range of oscillations correlated with some features of the reported ‘mystical’ experience. Further downstream, Jefsen et al (2021) investigate the acute effects of psilocybin on the expression of 46 neuroplasticity related genes in the prefrontal cortex and hippocampi of rats, showing rapid expression in plasticity promoting genes, more so in the prefrontal cortex (where 5-HT2A is densely expressed). Yet, 5-HT2A is but one modulator, and Inserra et al (2021) show that LSD modulates neuronal activity in both the reticular and mediodorsal thalamus in part due to its action as a type 2 dopamine receptor agonist.…”