Psilocybin Induced Transcriptional Response in Mouse Medial Prefrontal Cortex

Depression is a leading mental health problem worldwide. Many patients do not respond well to conventional treatment. Clinical trials suggest psilocybin as a potential alternative yet the mechanism of psilocybin remains poorly understood. Here we examined the behavioral and transcriptomic effects of psilocybin in mice. We found that a single injection of psilocybin reduced anxiety-like behaviors in female mice 24 hours later. We then used single-cell RNA-sequencing to probe the transcriptional effects of psilocybin in female mice in the medial prefrontal cortex, a brain region impaired in depression and targeted by antidepressants. We found that L5 6 NP, a type of deep layer excitatory neuron, displayed the strongest transcriptional response to psilocybin. Further analysis suggested that psilocybin reduced signaling from the inhibitory neurons and that psilocybin induced the expression of plasticity genes in neurons. Overall our work suggests that psilocybin increases neuroplasticity by inducing transcriptional changes in specific cell populations in the mouse prefrontal cortex and potential molecular mechanisms for the anti-depressant potential of psilocybin.