Quantitative tracking of trans-synaptic nose-to-brain transport of nanoparticles and its modulation by odor,aging,and Parkinson’s disease

Nanoparticles(NPs)can be transported via the nose-to-brain(N_(2)B)route.Nonetheless,quantitative data on their spatiotemporal dynamics and regulation of the N_(2)B transport are largely lacking.We surveyed metal oxide/hydroxide NPs as magnetic resonance imaging(MRI)contrasts for quantitative N_(2)B tracking.NPs containing divalent transition metals were the only ones capable of N_(2)B transmission.Using T1-weighted(T1W)MRI,we showed that Mn_(3)O_(4)-NPs were readily engulfed by olfactory receptor neurons(ORNs)without disrupting olfactory sensing,we mapped their N_(2)B trajectory.Within neurons,the Mn_(3)O_(4)-NPs were localized to the cytosol,mitochondria,vesicles,moved at mixed fast and slow axonal transport velocities intraand extra-vesicularly through ORNs.The NPs’axonal transport is dependent on neuronal activity and microtubule integrity.The Mn_(3)O_(4)-NPs were trans-synaptically transmitted through at least four synapses across the olfactory tract.Trans-synaptic transmission of the NPs was dependent on N-type Ca^(2+)channels and NMDA receptors but blocked by GABAB receptor activation.A five-parameter Weibull signal increase/decrease model fitted to the T1W MRI data allowed for estimating kinetic parameters of Mn_(3)O_(4)-NP accumulation/elimination.Absolute and relative accumulation rates,but not elimination,correlated negatively with the number of synapses from ORNs,indicating a coupling of the NPs’N_(2)B transport with spontaneous neuronal activity.Accordingly,olfactory stimuli(2,5-dimethylpyrazine and acetophenone)significantly modulated and rerouted the Mn_(3)O_(4)-NP N_(2)B transport odor specifically.Finally,the NPs’trans-synaptic transmission was impaired by aging and the onset of Parkinson’s disease.These data suggest new approaches to diagnostics,functional neuroimaging,controlling N_(2)B drug delivery.