ABSTRACT
Background Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity.
Methods Whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brainwide in situ hybridization data.
Results Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe, lateral habenula, and insular cortex for psilocybin and retrosplenial cortex for ketamine. Correlation of psilocybin’s effects with gene expression highlighted potential roles of 5-HT2A and GluN2B subunit of NMDA receptors.
Conclusions The systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a valuable resource that highlights previously underappreciated regions for future investigations. By identifying regions with similar and disparate effects, the results provide insights into how psilocybin and ketamine may produce their rapid-acting and long-lasting therapeutic effects.
Competing Interest Statement
A.C.K. serves on the scientific advisory board for Empyrean Neuroscience. No-cost compounds were provided to A.C.K. for research by Usona Institute. The authors declare no other competing interests or disclosures.
