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Perivascular AQPR4 Localization Cortex Hippocampus Neuroinflammatory environment in mouse model of high altitude and traumatic brain injury: novel therapeutic opportunities Kathleen Whiting1,2, 8, Caroline A. Browne5,8, Dara L. Dickstein1,4,7,8, Tara Barvir2,8, Jamaine Barnie2, Xiufen Xu2,8, Shalini Jaiswal3,7,8, Fritz Lischka6,8, Alexandru Korotcov3,7,8, Andrew Knutsen3,7,8, Nathan P. Cramer1,2,8, Vassiliy Tsytsarev2,5,8, Juan Wang4,7,8, Jeffrey J. Iliff9, Bernard J. Dardzinski1,3,7, Daniel P. Perl1,4,7 and Zygmunt Galdzicki1,2,7 1Graduate Program in Neuroscience, 2Department of Anatomy, Physiology and Genetics, 3Department of Radiology and Radiological Sciences, 4Department of Pathology, 5Department of Pharmacology, 6Biomedical Instrumentation Center, 7Center for Neuroscience and Regenerative Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 8The Henry M Jackson Foundation for the Advancement of Military Health, 9VA Puget Sound Health Care System, University of Washington School of Medicine The USUHS IACUC approved all procedures in this study. C57BL/6J mice, age ~12-14 weeks were maintained under a 12- hour reverse light/dark cycle with standard food and water available ad libitum unless specified. Changes in neurovascular structure were evaluated through microCT imaging, and distinct regional differences in microglia phenotypes through light-sheet imaging of Cx3Cr1-GFP mice. MicroCT images were co-registered to a mouse brain atlas and used to evaluate specific regions of interest and then analyzed using Vesselucida software (MBF) to quantify vascular changes including surface area, volume, diameter, length, tortuosity, and branching. MRI experiments were conducted using a 7 T Bruker Biospec 70/20 (Bruker Biospin, Billerica, MA) equipped with high-performance actively shielded gradients (660 mT/m) with integrated shim coils. In vivo 2-photon imaging with a cranial window was used to evaluate arteria, RITM0028595, The incidence of traumatic brain injury (TBI) among active-duty military personnel remains a significant medical concern that impacts operational readiness and the general well-being of service members. Activeduty personnel are frequently exposed to austere and stressful conditions during military operations, including high altitude (HA). HA is characterized by hypobaric hypoxia (HH) reducing oxygen availability that may result cerebral and pulmonary edema. Even a short exposure may result in subclinical symptoms impacting brain structure/function, such as a decline in cognition and sleep. There is limited information in the literature regarding the impact of HA-associated alterations in physiology on the neurobehavioral sequelae triggered by TBI. Our mouse model of HA replicates many of the physiological and behavioral alterations observed in humans, including elevated angiogenesis and BBB leakage, increased microglial phagocytosis, altered synaptic protein expression levels and astrogliosis, white matter abnormalities and deficits in hippocampal mediated behavior (Cramer et al. 2019; Sharma et al. 2019). We have also shown that repetitive closed-head injury affected hippocampal function by promoting a remodeling of excitatory and inhibitory synaptic inputs leading to impairment in hippocampal-dependent tasks and synaptic plasticity (Logue et al. 2016). In this study, the role of inflammation and neurovascular adaptive responses to HA are investigated. We hypothesized that microglia mediate the HA-associated pathophysiological changes in brain neurovasculature and neuronal circuitry following TBI.