Activity-Dependent Neural Rewiring: Mechanisms of Psilocybin-Induced Cortical Network Reorganization

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.