Psilocybin, the psychoactive compound in magic mushrooms, triggers network-specific neural rewiring that is activity-dependent and programmable. Using genetically modified rabies virus for monosynaptic circuit tracing, researchers discovered that psilocybin strengthens sensory-motor pathways while weakening cortical-cortical feedback loops linked to rumination and depression. Sensory regions showed up to 10% increases in connectivity, and self-referential regions exhibited up to 15% decreases. Neural activity during the psilocybin window determines which circuits are strengthened or weakened, suggesting therapeutic interventions could be optimized by controlling sensory and cognitive experiences during treatment. These findings provide mechanistic insights into psilocybin’s rapid antidepressant effects.
Psilocybin, a psychedelic compound, triggers activity-dependent rewiring of large-scale cortical networks. Using monosynaptic rabies viral tracing in mice, researchers mapped brain-wide inputs to pyramidal neurons in the dorsal medial frontal cortex. Psilocybin strengthened pathways routing sensory and retrosplenial inputs to subcortical targets while weakening cortico-cortical recurrent loops. This reorganization depends on neural activity during drug administration, shown through chemogenetic silencing. These findings offer insights into psychedelic mechanisms and suggest combining targeted neuromodulation with psychedelic treatment to enhance therapeutic outcomes for mental health disorders.