Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks
Quan Jiang, Ling-Xiao Shao, Shenqin Yao, Neil K. Savalia, Annie-Kim Gilbert, Pasha A. Davoudian, Jack D. Nothnagel, Guilian Tian, Tin Shing Hung, H. M. Lai, Kevin T. Beier, Hongkui Zeng, Alex C. Kwan
Cell December 5, 2025 DOI: 10.1016/j.cell.2025.11.009 via OpenAlex
Summary
AI-generated from the abstractA 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.
Study at a glance
| Characteristics | Experimental study in mice Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Dose | one dose |
| Topics | Default mode network Neuroplasticity Psilocybin |
| Keywords | Dendritic spine Nerve net Gene silencing |
| Citations | 15 |
| Key finding | Psilocybin induces network-specific strengthening of inputs from perceptual and medial regions to subcortical targets while weakening cortico-cortical recurrent loops, dependent on drug-evoked spiking activity. |
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.