@article{Romashchenko2023, 
author = {Alexander V. Romashchenko and Dmitrii V. Petrovskii and Sergey Yu. Trotsky and Ksenia N. Morozova and Nina B. Illarionova and Maria V. Zhukova and Elena V. Kiseleva and Marina B. Sharapova and Daniil S. Zuev and Konstantin E. Kuper and Sergey Yu. Taskaev and Anna I. Kasatova and Dmitrii A. Kasatov and Olga I. Solovieva and Ivan A. Razumov and Ludmila A. Gerlinskaya and Mikhail P. Moshkin and Yuri M. Moshkin},
title = {Quantitative tracking of trans-synaptic nose-to-brain transport of nanoparticles and its modulation by odor, aging, and Parkinson’s disease},
year = {2023},
journal = {Nano Research},
volume = {16},
number = {5},
pages = {7119-7133},
keywords = {Mn3O4 nanoparticles, magnetic resonance imaging (MRI), nose-to-brain transport, trans-synaptic transmission, olfactory stimulation},
url = {https://www.sciopen.com/article/10.1007/s12274-022-5302-6},
doi = {10.1007/s12274-022-5302-6},
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 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.}
}