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

作　　者：Alexander V.Romashchenko Dmitrii V.Petrovskii Sergey Yu.Trotsky Ksenia N.Morozova Nina B.Illarionova Maria V.Zhukova Elena V.Kiseleva Marina B.Sharapova Daniil S.Zuev Konstantin E.Kuper Sergey Yu.Taskaev Anna I.Kasatova Dmitrii A.Kasatov Olga I.Solovieva Ivan A.Razumov Ludmila A.Gerlinskaya Mikhail P.Moshkin Yuri M.Moshkin 

机构地区：[1]The Federal Research Center Institute of Cytology and Genetics,SB RAS,Academician Lavrentiev Avenue,10,Novosibirsk 630090,Russia [2]International tomography center,Institutskaya st.,3A,Novosibirsk 630090,Russia [3]G.K.Boreskov Institute of Catalysis,SB RAS,Academician Lavrentiev Avenue,5,Novosibirsk 630090,Russia [4]The Federal Research Center Budker Institute of Nuclear Physics,SB RAS,Academician Lavrentiev Avenue,11,Novosibirsk 630090,Russia [5]Institute of Computational Technologies,Academician M.A.Lavrentiev avenue,6,Novosibirsk 630090,Russia [6]Institute of Gene Biology,Russian Academy of Sciences,Moscow 117334,Russia [7]Institute of Molecular and Cellular Biology,SB RAS,Acad.Lavrentiev Ave,8/2,Novosibirsk 630090,Russia [8]Federal Research Centre of Biological Systems and Agrotechnologies,RAS,st.January 9,29,Orenburg 460000,Russia

出　　处：《Nano Research》2023年第5期7119-7133,共15页纳米研究（英文版）

基　　金：the Russian Foundation for Basic Research RFBR(No.20-16-00078);the Centers of Collective Use“National Center of Catalyst Research”of Boreskov Institute of Catalysis SB RAS and by the budget project(No.FWNR-2022-0023 and project FWNR-2022-0004);the equipment of the Center for Genetic Resources of Laboratory Animals at ICG SB RAS,supported by the Ministry of Education and Science of Russia(Unique identifier of the project RFMEFI62119X0023);TEM imaging was performed at the Microscopy Center of Biological Subjects ICG SB RAS(project#0259-2021-0011)。

摘　　要：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.

关 键 词：Mn_(3)O_(4)nanoparticles magnetic resonance imaging(MRI) nose-to-brain transport trans-synaptic transmission olfactory stimulation 

分 类 号：R742.5[医药卫生—神经病学与精神病学] TB383[医药卫生—临床医学]