Effects of psilocybin on mouse brain microstructure

There is surging interest in the therapeutic potential of psychedelic compounds like psilocybin in the treatment of psychiatric illnesses like major depressive disorder (MDD). Recent studies point to the rapid antidepressant effect of psilocybin; however, the biological mechanisms underlying these differences remain unknown. This study determines the feasibility of using diffusion MRI to characterize and define the potential spatiotemporal microstructural differences in the brain following psilocybin treatment in C57BL/6J male mice. 11-15 week-old C57BL/6J male mice were randomized to receive psilocybin, 6F-DET (6-fluoro-N,Ndiethyltryptamine), or saline and ex vivo imaged 24h (n=18) and 72h (n=18) post treatment. A one-way ANOVA with multiple comparison testing (Bonferroni correction) assessed diffusion metric differences (tractography, DTI, NODDI) between the three groups and was performed in the following regions of interest: amygdala, striatum, hippocampus, thalamus, primary visual cortex area, frontal association cortex, and medial prefrontal cortex at 24h and 72h post drug administration. Psilocybin treated mice demonstrated structural connectivity differences at 72h in the frontal association cortex (compared to saline, mean tract length increases, p=0.03). Psilocybin also induced microstructural differences at 24h post-injection in the primary visual cortex (compared to saline, MD increases, p=0.02) and 72h post-injection in the striatum (compared to saline; MD increases, p= 0.02, NDI decreases, p=0.02) and hippocampus (compared to saline; MD increases, p=0.04, NDI decreases, p=0.02). Diffusion microstructure imaging and white matter tractography are sensitive methods to detect and characterize the neural substrates and microstructural differences accompanying psilocybin treatment. These findings suggest the potential role for diffusion microstructure imaging to quantify the bioeffects of psychedelics like psilocybin on the brain, monitor treatment response, and identify salient clinical endpoints in an emerging therapeutic option for patients with MDD. dMRI= diffusion-weighted MRI; 6F-DET= 6-fluoro-N,N-diethyltryptamine; NODDI= neurite orientation dispersion and density imaging; DTI= diffusion tensor imaging; NDI= neurite density index; ODI= orientation dispersion index; FA= fractional anisotropy; MD= mean diffusivity; MTL= mean tract length; mPFC= medial prefrontal cortex.