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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| 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 Thalamus Synapse Cortex anatomy Cerebral cortex Biological neural network Bursting Perception |
| Citations | 15 |
| Key findings | 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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 13
- The science of psychedelic medicine. Nature Medicine February 6, 2026
- Psilocybin, From Ancestral Use to Therapeutic Potential: A Multidimensional Review of Its Pharmacological Basis and Current Perspectives Human Psychopharmacology: Clinical and Experimental September 1, 2026
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Classic psychedelics in obsessive–compulsive disorder: a circuit-based framework Nature Mental Health April 1, 2026
- Psilocybin Attenuates Cortical Representations of Aversion in the Mouse Auditory Cortex. bioRxiv : the preprint server for biology March 27, 2026
and 8 more in the library
Cites 29
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 24 more in the library