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

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.