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Abstract
Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There
are hints that the use of psychedelics can produce neural adaptations, although the
extent and timescale of the impact in a mammalian brain are unknown. In this study,
we used chronic two-photon microscopy to image longitudinally the apical dendritic
spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that
a single dose of psilocybin led to ∼10% increases in spine size and density, driven
by an elevated spine formation rate. The structural remodeling occurred quickly within
24 h and was persistent 1 month later. Psilocybin also ameliorated stress-related
behavioral deficit and elevated excitatory neurotransmission. Overall, the results
demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring,
potentially providing a structural trace for long-term integration of experiences
and lasting beneficial actions.