Traumatic brain injury (TBI) is a major health problem among US military service members and Veterans. Although many with mild TBI will recover within 1-2 weeks, those with moderate to severe TBI as well as nearly 50% of those with mild TBI will have persistent symptoms lasting for months. Understanding the risk factors involved in the persistent sequelae after TBI and the underlying molecular mechanisms will facilitate the development of novel therapeutics. One potential factor recently identified in a study of US military service members is pre-exposure to early stressful life experiences. Adverse childhood experiences are reported at significantly higher levels among military personnel and Veterans than civilians. A key mechanism linking chronic stress in early life to neurological problems in adulthood is immune dysregulation. Exposure to early life stress (ELS) enhances pro-inflammatory cytokine release by microglia in response to a subsequent inflammatory challenge. The goal of this proposal is to determine if ELS during development limits the recovery trajectory after a TBI that occurs in adulthood. Using brief daily maternal separation in rat pups to model ELS, we have found that ELS prior to TBI in adulthood increased interleukin-1β (IL-1β) levels and expression of the NLRP3 inflammasome, which is a multi-protein complex that results in cleavage and activation of IL-1β. Exposure of ELS prior to TBI also resulted in hippocampal atrophy, neuronal loss, and hippocampal-dependent learning deficits. In contrast, TBI alone without stress or ELS in non-injured animals did not increase IL-1β levels, nor were there observable learning deficits or pathology within the hippocampus. Treatment with an NLRP3 inflammasome inhibitor reversed these learning deficits and reduced hippocampal pathology and pro- inflammatory cytokine expression. In this proposal, we will test the hypothesis that ELS limits the recovery after TBI by increasing inflammatory signaling in microglia through the NLRP3 inflammasome, leading to the worsening of hippocampal pathology and the development of persistent learning and memory deficits. To test this hypothesis, the following aims are proposed: 1) To determine if ELS prior to TBI experienced in adulthood increases microglia activation, potentiates pro-inflammatory cytokine expression and activates the NLRP3 inflammasome, 2) To determine if ELS and TBI result in chronic behavioral problems and if these behavioral deficits can be improved with an NLRP3 inflammasome inhibitor, and 3) To determine if ELS exacerbates hippocampal neuronal and synaptic loss after TBI and if this can be reduced with an NLRP3 inflammasome inhibitor. These studies will determine whether stress in early childhood is a predisposing factor for the development of persistent neurological sequela after TBI. We will also test a promising therapeutic approach for TBI, an NLRP3 inflammasome inhibitor, to determine if this will reduce inflammation, prevent hipp...