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Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks.
Peer-reviewed Human StudyObservationalPubMedJournal ArticleJanuary 23, 2026PMID: 41352354DOI
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.
Authors (13)
LeadMeinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Allen Institute for Brain Science, Seattle, WA 98109, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06511, USA; Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT 06511, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT 06511, USA; Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT 06511, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.
Allen Institute for Brain Science, Seattle, WA 98109, USA.
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address: alex.kwan@cornell.edu.