Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks
Cell December 5, 2025 Quan Jiang, Ling-Xiao Shao, Shenqin Yao et al. 15 citations
A single dose of psilocybin causes structural remodeling of dendritic spines in the medial frontal cortex of mice. Using monosynaptic rabies tracing, the researchers mapped brain-wide inputs to frontal cortical pyramidal neurons and found that psilocybin's effect on connectivity is network specific: it strengthens routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on drug-evoked spiking activity, as silencing a presynaptic region during psilocybin administration disrupts the rewiring. These results reveal how psilocybin impacts large-scale cortical network connectivity and show that neural activity modulation can sculpt psychedelic-evoked plasticity.