Exposure to COVID-19 virus-like particles modulates firing patterns of cortical neurons in the mouse brain

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes a systemic infection that affects the central nervous system. However, its high infectivity makes comprehensive research with the active virus challenging. Here, we use virus-like particles (VLPs) to explore how exposure to SARS-CoV-2 proteins affects brain activity patterns in wild-type mice and in mice that express the human tau protein. VLP exposure elicits changes in corticosterone and distinct chemokine levels. Longitudinal two-photon microscopy recordings in primary somatosensory and motor cortices reveal substantial short-term increases in cortical activity in VLP-injected mice, with increased stimulus-evoked activity in both genotypes and elevated spontaneous activity in the human tau genotype only. Vehicle-injected human tau mice also show increases in cortical activity patterns. Over the following weeks, activity metrics partially subside but do not completely return to baseline levels. Overall, our data suggest that exposure to SARS-CoV-2 VLPs leads to strong short-term disruption of cortical activity patterns in mice with long-term residual effects. Middle-aged human tau mice, which have a more vulnerable genetic background and overexpression of the tau protein, exhibit more severe pathobiology and may be at risk for more adverse outcomes.