Sex-dependent developmental changes in behavior, brain structure, functional connectivity, and sensory perception following exposure to psilocybin during adolescence

Adolescent mice given psilocybin every other day from postnatal days 40-50 showed long-term changes in brain structure and function when tested in adulthood. Brain imaging revealed reduced volume and altered water diffusivity in several regions, with males more affected than females. Functional connectivity increased globally and regionally, notably between the prefrontal cortex and hypothalamus, thalamus, and midbrain. Mice showed reduced brain sensitivity to rewarding and aversive odors, and males had lower levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. Behaviorally, female mice showed reduced mobility in the open field test, while no differences appeared in the light/dark box test. These findings indicate that adolescent psilocybin exposure produces lasting developmental consequences, especially in males.

Study at a glance

Abstract

Psilocybin is a hallucinogen with complex neurobiological and behavioral effects. Underlying these effects are changes in brain neuroplasticity. We hypothesized psilocybin given during adolescence, a time of heightened neuroplasticity, particularly in the forebrain, would affect emotional behavior and the associated underlying neuroanatomy, neurocircuitry, and epigenetics. Female and male mice were given vehicle or 3.0 mg/kg psilocybin every other day by oral gavage from postnatal days 40-50 for a total of five exposures. Between postnatal days 90-120 mice were imaged and evaluated for affective behavior and perception of rewarding and aversive stimuli. MRI data from voxel-based morphometry, diffusion weighted imaging, and BOLD resting state functional connectivity were registered to a mouse 3D MRI atlas with 139 brain regions providing site-specific differences in global brain structure and functional connectivity between experimental groups. The prefrontal cortex was measured for changes in proteins associated with epigenetics. Mice showed no significant differences in the light/dark box test, but female mice exposed to psilocybin showed reduced mobility in the open field as compared to controls. Mice with early psilocybin exposure showed reduced brain sensitivity to both rewarding and aversive odors during scanning sessions. There were regional reductions in brain volume and alteration in water diffusivity affecting males more than females. Global and regional functional connectivity were increased in both sexes with the prefrontal cortex showing enhanced connections to the hypothalamus, thalamus and midbrain. Males showed reduced levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. The pronounced changes in brain volume, water diffusivity - a surrogate marker of gray matter microarchitecture, increase in functional connectivity, altered perception of rewarding and aversive stimuli and altered levels of protein markers of neuroplasticity provide compelling evidence that exposure to psilocybin during adolescence has long term developmental consequences, particularly in males.