PROJECT SUMMARY Given the current global COVID-19 pandemic, as well as documented challenges in long-COVID health burdens among people of lower socioeconomic backgrounds, understanding the cellular and molecular mechanisms responsible for SARS-CoV-2-induced neurological disorders is of fundamental importance. We recently developed a mouse SARS-CoV-2 infection model (SARS2-N501YMA30) showing alteration in mice behaviors fourteen days post-infection, allowing us to study long-term behavioral changes caused by SARS-CoV-2. Four days after the virus infection, we detected SARS-CoV-2 genomic RNA in brain tissues. In addition, SARS-CoV-2 dsRNA was detected exclusively within neurons, along with vigorous microglia activation. These data together with previous works might implicate the involvement of brain immune cells, such as microglia. Also, these preliminary data suggest a novel mechanism of SARS-CoV-2 infection- induced behavioral changes in mice. Thus, the goal of this proposal is to elucidate the mechanisms by which SARS-CoV-2 modulates neuronal activity in mice. This proposal describes three distinct aims to reach this goal. The first aim focuses on determining whether SARS2-N501YMA30 infection induces neuronal hyperactivity in mice. The second aim will determine how SARS2-N501YMA30 activates microglia via microglia-neuron interaction. The third aim will determine how microglia activation excites surrounding excitatory neurons in response to SARS2-N501YMA30 infection. Uncovering the cellular and molecular mechanisms by which SARS-CoV-2 alters neuronal activity through regulating neuron-microglia interaction will facilitate the development of therapeutic strategies to minimize long-COVID suffering, health disparity, and mortality from the COVID-19 pandemic.

PROJECT NARRATIVE The current global COVID-19 pandemic is creating long COVID symptoms for many Americans, especially those with lower socioeconomic backgrounds. In this proposal, we will uncover the cellular and molecular mechanisms by which SARS-CoV-2 alters neuronal functions and define how microglia- neuron interaction plays a key role in this process. Doing so will reveal new therapeutic strategies to minimize long COVID suffering under the current pandemic.