PROJECT SUMMARY Mild traumatic brain injuries (mTBIs) affect millions per year, leaving 10-40% of patients with long-lasting (>1 month) physical, emotional, psychological, and cognitive symptoms for which effective therapeutic strategies are lacking. Moreover, repetitive mTBI (rmTBI) can lead to cumulative severity and duration of adverse consequences. Clinical and preclinical studies have shown that the spectrum of neurological sequelae seen post-injury cannot be explained by biomechanical impact forces alone. Injury mechanisms underlying neurological symptoms after repetitive mild traumatic brain injury (rmTBI) are poorly understood and may be distinct from more severe forms of TBI. Working together, Drs. Wood and Buckley (co-PIs) have recently discovered that neuronal p38 MAPK phosphorylation is acutely up-regulated in mice predicted to have worse cognitive outcomes after rmTBI. p38 MAPK is a stress-response pathway with a well-established pro- inflammatory role in microglia after TBI. However, there is a gap in knowledge on the role of neuronal p38 MAPK phosphorylation in regulating response to injury that leads to cellular and cognitive dysfunction after TBI. Our overall hypothesis is that p38 MAPK phosphorylation, especially within neurons, drives both 1) acute changes in cytokine expression, microglia activation, and cerebral blood flow and 2) chronic changes in microglia and cognitive deficits after rmTBI. Given limited knowledge on the role of neuronal phospho-signaling in driving these neuroinflammatory, cognitive, and physiologic changes after TBI, the goal of this proposal is to expand our knowledge on the role of p38 MAPK phosphorylation on brain sequalae following repetitive mild TBI. Thus, the investigative team has designed specific aims to: (Aim 1) define the role of neuronal p38 MAPK in driving neuroinflammation after rmTBI, including cytokine expression and microglial phenotype; (Aim 2) define the role of neuronal p38 MAPK in driving longer term cognitive outcomes up to 12 weeks post injury, test the ability of transient pharmacologic inhibition of p38 MAPK to protect cognitive outcomes, and determine if microglia mediate the effects of neuronal p38 MAPK on cognitive outcomes; (Aim 3) determine if neuronal p38 MAPK or a neuronally expressed vasomodulatory cytokine (IL-17) drive changes in CBF after repetitive mild TBI. The proposed work will be completed by a team with expertise in systems analysis of neural immune signaling (Wood), pre-clinical models of traumatic brain injury and measurement of CBF (Buckley), microglial phenotyping (Rangaraju) and mechanisms of cerebral blood flow regulation (Jo). Completion of these aims will yield unprecedented insight into the role of neuronal phospho-signaling in driving sequalae following repetitive mild TBI. Moreover, since this work will test a translationally relevant drug for inhibition of p38 MAPK, success of these aims will present a rapidly translatable approach to treatment of re...