Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks
Cell – December 05, 2025
Source: OpenAlex
Summary
A single dose of psilocybin dramatically reconfigures brain connections, offering new insights into its therapeutic potential. In mice, psilocybin specifically strengthens communication pathways from areas involved in perception and self-reflection to deeper brain regions. Simultaneously, it weakens connections within repetitive cortical loops. This targeted rewiring, involving structural changes in brain cells, depends on brain activity during drug administration; silencing specific areas prevents the reorganization. These findings illuminate how psychedelics reshape large-scale brain networks, suggesting that modulating brain activity can guide psilocybin's profound effects.
Abstract
Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin's effect on connectivity is network specific, strengthening the 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 the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.