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 (N2B) route. Nonetheless, quantitative data on their spatiotemporal dynamics and regulation of the N2B transport are largely lacking. We surveyed metal oxide/hydroxide NPs as magnetic resonance imaging (MRI) contrasts for quantitative N2B tracking. NPs containing divalent transition metals were the only ones capable of N2B transmission. Using T1-weighted (T1W) MRI, we showed that Mn3O4-NPs were readily engulfed by olfactory receptor neurons (ORNs) without disrupting olfactory sensing, and we mapped their N2B trajectory. Within neurons, the Mn3O4-NPs were localized to the cytosol, mitochondria, and vesicles, and moved at mixed fast and slow axonal transport velocities intra- and extra-vesicularly through ORNs. The NPs’ axonal transport is dependent on neuronal activity and microtubule integrity. The Mn3O4-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 Ca2+ 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 Mn3O4-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’ N2B transport with spontaneous neuronal activity. Accordingly, olfactory stimuli (2,5-dimethylpyrazine and acetophenone) significantly modulated and rerouted the Mn3O4-NP N2B 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, and controlling N2B drug delivery.