Exposure to manganese during juvenile development increases microglial activation in the hippocampus following systemic infection with A/California/04/2009 Influenza A H1N1 virus.

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Up to 80% of patients with Parkinson's Disease (PD) develop dementia within 20 years of diagnosis. Although the etiology of PD and related neurodegenerative disorders is poorly understood, risk factors including environmental toxicants and viral infections are linked to disease onset and progression. Exposure to high doses of the essential element, manganese (Mn), causes neurotoxicity associated with parkinsonian symptoms and cognitive impairment in humans. Additionally, epidemiologic studies indicate that viral infections increase risk of developing PD. Previously, our lab demonstrated that mice exposed to Mn during juvenile development showed greater neuroinflammatory changes in microglia within the substantia nigra following systemic infection with H1N1 influenza virus (California/04/09 influenza A) than mice infected without prior exposure to Mn. In the present study, this murine dual-hit model was employed to investigate how juvenile Mn exposure alters H1N1-induced neuropathology and glial morphology in the hippocampus. Mice were exposed to Mn in drinking water from post-natal day 21-51 and then intranasally infected with 103 TCID50 A/California/04/2009 H1N1. To assess histopathology following this exposure paradigm, we performed high-content microscopy and machine learning-based image analysis of H&E and IHC-stained sections spanning the hippocampus to quantify pyknotic neurons and reactive microglia. We report a significant increase in the number of pyknotic neurons in the dentate gyrus as well as morphologic changes in microglia that are consistent with inflammatory activation. Our findings highlight the capacity of combined juvenile manganese exposure and adult viral infection to induce substantial microgliosis in the hippocampus.

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