Abstract This proposal seeks to determine the regulation of microglial type I interferon signaling following traumatic brain injury (TBI) and to identify how this affects neuroinflammation, neurodegeneration, and the neurocognitive sequelae following TBI. TBI is a major public health problem, representing a leading cause of death and disability from childhood through middle adulthood. Unfortunately, pharmacologic therapies for TBI are non-existant. Treatment strategies that target specific secondary injury cascades like dysregulated neuroinflammation are critically needed. Microglia, the primary immune cells of the CNS, persist in an activated state for months and years following a single TBI and are associated with neurodegeneration. Mechanisms that result in sustained, damaging neuroinflammation vs resolution of inflammation are unclear. Our recently published work, however, demonstrated that the microglial transcriptome at a subacute time point following TBI was highly enriched for type I interferon stimulated genes raising the question of if type I interferons are key signaling molecules resulting in sustained, dysregulated microglial activation. The types and cell sources of type I interferons activating microglia following TBI are unknown. Similarly, the specific effects of type I interferons on sustained microglial reactivity and the subsequent mechanisms of microglial mediated neurodegeneration and neurologic dysfunction following TBI remain unknown. Using a lateral fluid percussion injury model of TBI in mice, combined with sophisticated mouse genetics, our data will uncover cell-specific effects of type I interferon signaling on secondary injury. The hypothesis of this proposal is that multiple type I IFNs drive development of dysregulated microglia subsets, immune cell recruitment, and the subsequent neurodegeneration and neurobehavioral impairments that occur after TBI. In the first aim, we will identify the types and cell-sources of type I IFNs driving persistent microglial and CNS interferon stimulated gene expression following TBI. In the second aim, we will determine the impact of type I IFN signaling on microglial subsets and their transcriptional activation following TBI. Finally, in the third aim, we will determine the mechanisms by which type I interferon activated microglial impact neuropathology and neurocognitive dysfunction following TBI, including through their recruitment of CD8+ T cells. As TBI is a leading, untreatable cause of death and disability in the US, there is a critical need for further study of the specific mechanisms of secondary injury so that ultimately, new therapies may be discovered.