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bioRxiv · 10.1101/2023.10.02.560570

SARS-CoV-2 neurotropism-induced anxiety and depression-like behaviors require Microglia activation

Ge, Q.·Zhou, S.·Porras, J.·Fu, P.·Wang, T.·Du, J.·Li, K.
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Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with a wide range of "long COVID" neurological symptoms. However, the mechanisms governing SARS-CoV-2 neurotropism and its effects on long-term behavioral changes remain poorly understood. Using a highly virulent mouse-adapted SARS-CoV-2 strain, denoted as SARS2-N501YMA30, we demonstrated that intranasal inoculation of SARS2-N501YMA30 results in viral dissemination to multiple brain regions, including the amygdala and hippocampus. Behavioral assays indicated a marked elevation in anxiety- and depression-like behaviors post infection. A comparative analysis of RNA expression profiles disclosed alterations in the post-infected brains. Additionally, we observed dendritic spine remodeling on neurons within the amygdala after infection. Infection with SARS2-N501YMA30 was associated with microglial activation and a subsequent increase in microglia-dependent neuronal activity in the amygdala. Pharmacological inhibition of microglial activity subsequent to viral spike inoculation mitigates microglia-dependent neuronal hyperactivity. Transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating microglia-driven neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Overall, these data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.

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Ge, Q., Zhou, S., Porras, J., Fu, P., Wang, T., Du, J., Li, K.. 2023-10-03. SARS-CoV-2 neurotropism-induced anxiety and depression-like behaviors require Microglia activation. https://doi.org/10.1101/2023.10.02.560570

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