PROJECT SUMMARY/ABSTRACT Viral infections are now recognized as risk factors for diseases of progressive pathological forgetting, supporting a new paradigm in neuroimmunology whereby innate immune molecules that function as modulators of a variety of normal CNS functions induce neurodegenerative diseases during host-pathogen responses. Studying virus-mediated cognitive dysfunction through the multidisciplinary prism of immunology, neuroscience, and virology is critical for the identification of novel mechanisms of disease, discovery of neuroimaging tools and therapeutic treatments for a wide range of diseases of memory disorder. In my laboratory we made unanticipated, paradigm-shifting discoveries of the roles of CNS infiltrating mononuclear cells in microglial-mediated synapse elimination, disrupted adult neurogenesis, and generation of neurotoxic astrocytes using novel models of recovery from encephalitogenic flaviviruses, West Nile (WNV) and Zika (ZIKV) viruses. We identified classical complement proteins and cytokine receptor signaling as novel molecular mediators that regulate synapse elimination, neural stem cell (NSC) fates, neuron-microglia and microglia- astrocyte crosstalk within cortical structures that regulate memory formation and maintenance. We have also begun leveraging novel neuroimaging modalities to develop biomarkers that may be used to predict and monitor patients at risk for memory disorders. Our aim is to understand the mechanisms that induce alterations in synaptic connections and methods of repair that contribute to disruption of neuronal networks after recovery from viral infections. Our research program focuses on three broad areas related to the roles and regulation of innate immune molecules involved in spatial learning using novel murine models of post-infectious cognitive dysfunction. First, using genetic, pharmacologic and PET-MRI, we will identify and define molecular interactions between T cells and microglia or neurons that drive the generation and maintenance of resident memory T cells that promote cognitive dysfunction. We will use scRNAseq under BSL3 conditions to screen for genes and pathways to be targeted via cell-specific deletion of cytokine or chemokine receptors, or administration of agents that inhibit or enhance pathways. We will also develop diagnostic tools that employ ABSL3 PET-MRI. Second, we will define how microglia-astrocyte-NSC interactions in the context of recovery from CNS viral infections limit repair and recovery. We will use global and conditional gene targeting in mice to delineate the in vivo roles of cytokines in neural cell types that regulate astrocyte inflammasome activation and its relationship to neuronal and synapse recovery. We will also define innate immune mechanisms that direct and maintain astrogenosis during acute viral infection and recovery using PET-MRI detection of P2X7R, a marker of reactive astrocytes. Finally, will utilize reporter mice/fate mapping, bone marrow ch...