Acute particulate matter (PM10) exposure selectively triggers behavioral alterations in the presymptomatic Experimental Autoimmune Encephalomyelitis (EAE) mouse model of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic disease of the Central Nervous System, where neuroinflammation and autoimmune response against myelin lead to functional impairments, cognitive and psychiatric symptoms. Exposure to air pollution – in particular to peaks of particulate matter (PM) – has been associated with an increase of hospital admissions for MS onset and relapses and exacerbated neuroinflammation in MS patients. Here, in the MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we tested the hypothesis that exposure to PM10 might influence the disease course and severity in individuals with a predisposing background. Short-term PM10 exposures - occurring either before immunization or during the pre-symptomatic phase - did not modify disease manifestation in EAE mice, as assessed by clinical and neuropathological analyses. Yet, presymptomatic EAE – but not healthy - mice selectively showed increased disinhibited, risk-taking and novelty-seeking behaviors early after being exposed to PM10. These data show a selective vulnerability of immunologically primed mice toward the effects of PM10, occurring before the emergence of overt motor impairment and presenting as specific behavioral alterations. Competing Interest Statement The authors have declared no competing interest. Footnotes

updated; Figures 3 and 5 revised; author list updated; Supplemental files updates List of abbreviations - 5-HT - 5-hydroxytryptamine (Serotonin) - AEA - Anandamide - AOBS - Acoustic-optical Beam Splitter - BBB - Blood Brain Barrier - CNS - Central Nervous System - Comt - Catechol-O-Methyltransferase - CSF - Cerebrospinal Fluid - Ctrl - Control DA - Dopamine - DAPI - 4,6-diamidino-2-phenylindole - Dbh - Dopamine Beta Hydroxylase - DDA - Data Dependent Acquisition - DRD1 - Dopamine Receptor D1 - DRD2 - Dopamine Receptor D2 - EAE - Experimental Autoimmune Encephalomyelitis - EPM test - Elevated Plus Maze Test - EVs - Extracellular Vesicles - FTMS - Fourier Transformer Mass Spectrometry - GFAP - Glial Fibrillary Acid Protein - HPLC - High Performance liquid Chromatography - HRMS - High Resolution Mass Spectrometry - IBA1 - Ionized Calcium-binding Adapter molecule 1 IL-1α - Interleukin 1 alpha - IL-1β - Interleukin 1 Beta IL-6 - Interleukin 6 - INF-γ - Interferon Gamma - LOD - Limit of Detectable - LOQ - Limit of Quantification - Lrrk2 - Leucine-rich Repeat Kinase 2 - MaoA - Monoamine Oxiade A - MaoB - Monoamine Oxidase B - MBP - Myelin Basic Protein - MOG - Myelin Oligodendrocyte Glycoprotein - MRI - Magnetic Resonance Imaging - MS - Multiple Sclerosis - MS/MS - Tandem Mass Spectrometry - NOL test - Novel Object Location test - OF test - Open Field test - Olig 2 - Oligodendrocyte Transcription Factor 2 - PB - Phosphate Buffer - PBS - Phosphate Buffer Saline - PFC - Prefrontal Cortex - PM - Particulate Matter - Prkn - Parkin RBR E3 Ubiquitin Protein Ligase - qRT-PCR - quantitative Real Time Polymerase Chain Reaction - Rit2 - Ras-like without CAAX 2 - ROI - Region of Interest - RP column - Reverse Phase column - RT - Reflectance/Transmission - SCoRe - Spectral Confocal Reflectance Microscopy - SE - Standard Error - Slc18a2 - Solute Carrier family 18 member 2 - Slc6a3 - Solute Carrier family 6 member 3 - SPE column - Solid Phase Extraction column - Th - Tyrosine Hydroxylase - TNF-α - Tumor Necrosis Factor Alpha - TOF - Time of Flight - Tph2 - Tryptophan hydroxylase 2 - TST - Tail Suspension Test - VIP-HESI - Vacuum Insulated Probe Heated Electrospray Ionization - Vps35 - VPS35 Retromer Complex Component