Activity-Dependent Neural Rewiring: Mechanisms of Psilocybin-Induced Cortical Network Reorganization
Zenodo (CERN European Organization for Nuclear Research) February 6, 2026 preprint DOI: 10.5281/zenodo.18501568 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review |
|---|---|
| Population | Mice |
| Intervention | Psilocybin |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Neuromodulation Neural activity Sensory system Mechanism biology Gene silencing Synapse Biological neural network Dorsum Schizophrenia object-oriented programming Nerve net |
| Key findings | Psilocybin induces highly network-specific reorganization of cortical connectivity, strengthening sensory and retrosplenial pathways to subcortical targets while weakening cortico-cortical recurrent loops, dependent on neural activity during administration. |
Abstract
Psychedelic compounds, particularly psilocybin, have demonstrated remarkable therapeutic potential for mental health disorders through mechanisms involving structural neural plasticity. This comprehensive review examines recent breakthrough research revealing how psilocybin triggers activity-dependent rewiring of large-scale cortical networks. Using monosynaptic rabies viral tracing, researchers have mapped the brain-wide distribution of inputs to pyramidal neurons in the mouse dorsal medial frontal cortex, discovering that psilocybin induces highly network-specific reorganization. The drug strengthens pathways routing sensory and retrosplenial inputs to subcortical targets while weakening cortico-cortical recurrent loops. Critically, this rewiring depends on neural activity patterns during drug administration, as demonstrated through chemogenetic silencing experiments. These findings provide crucial insights into psychedelic mechanisms and suggest novel approaches for enhancing therapeutic outcomes through targeted neuromodulation combined with psychedelic treatment. This paper synthesizes the current understanding of psilocybin’s effects on neural connectivity, discusses implications for mental health treatment, and explores future directions for optimizing psychedelic-assisted therapy.
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 |