Quantitative tracking of trans-synaptic nose-to-brain transport of nanoparticles and its modulation by odor, aging, and Parkinson’s disease
А. В. Ромащенко, Д. В. Петровский, Sergey Yu. Trotsky, Ksenia N. Morozova, Nina B. Illarionova, Mariya Zhukova, Елена Киселева, M. B. Sharapova, Daniil Zuev, К. Э. Купер, S. Yu. Taskaev, А. I. Kasatova, D. A. Kasatov, Olga I. Solovieva, И. А. Разумов, L. A. Gerlinskaya, М. П. Мошкин, Yuri M. Moshkin
Abstract
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 T 1 -weighted (T 1 W) MRI, we showed that Mn 3 O 4 -NPs were readily engulfed by olfactory receptor neurons (ORNs) without disrupting olfactory sensing, and we mapped their N2B trajectory. Within neurons, the Mn 3 O 4 -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 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 GABA B receptor activation. A five-parameter Weibull signal increase/decrease model fitted to the T 1 W 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’ N2B transport with spontaneous neuronal activity. Accordingly, olfactory stimuli (2,5-dimethylpyrazine and acetophenone) significantly modulated and rerouted the Mn 3 O 4 -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.