Psilocybin rewires neural circuits in mice through a pathway separable from psychedelic behavioral effects

Research from the University of California, Santa Cruz, shows that psilocybin rapidly reshapes neural circuits in living mice by increasing the formation and maturation of dendritic spines while also removing some existing connections. The effects differed by brain state: healthy mice later returned toward baseline connectivity, whereas chronically stressed mice formed more new spines and were protected from stress-related synaptic loss. Experiments identified serotonin 2A receptors on Layer 5 pyramidal neurons as necessary and sufficient for the structural changes, but not for the rodent head-twitch response commonly used as a marker of psychedelic activity. This separation suggests that non-hallucinogenic compounds might reproduce some neuroplastic and therapeutic effects. However, the findings are limited to mice, and it remains unknown whether the mechanism translates to humans or can treat depression or PTSD.