The relationship of retinal and brain pathology in a mouse model of closed-head concussive impact injury
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Exposure to repetitive closed-head impact injuries are associated with later development of chronic traumatic encephalopathy (CTE), a progressive tau protein neurodegenerative disease. Increased cumulative exposure to closed-head impact injuries correlates with greater risk of developing CTE. No treatments or validated diagnostic biomarkers for CTE currently exist due to a lack of understanding the mechanistic pathways that underlie the progression of aberrant neuropathology after closed-head injury. Animal models with biological endpoints that match the human neuropathology of closed-head injury could help to understand the biological mechanisms underpinning the development of CTE. To address this issue, we created a novel model of closed-head impact injury. We hypothesized that closed-head impact injury creates focal damage in the ipsilateral cortex and retina. The retina is an optically accessible tissue and shares developmental origins with the brain. The optical accessibility of the retina allows for the observation of pathological changes and functional deficits after closed-head injury. We found that closed-head injury resulted in acute and transient neurobehavioral deficits similar to signs of concussion in humans. After closed-head injury, we observed focal damage to the ipsilateral cortex which included microvascular disruption, neuroinflammation, axonopathy, and tauopathy. We also observed bilateral electrophysiological deficits. In the retina, we observed focal ipsilateral microgliosis and ipsilateral electroretinography deficits. The pathology and functionality of the cortex and retina were normal in sham mice. Given the identification of pathological and functional deficits, we selected several in vivo biomarkers of traumatic brain injury (TBI) for study. Closed-head injured mice could be distinguished from sham mice using a peripheral blood biomarker, by magnetic resonance imaging assessment of the blood-brain barrier, and with fluorescent adaptive optics scanning laser ophthalmoscopy observation of retinal microglia. Our novel animal model of closed-head injury produces traumatic brain injury pathology consistent with human case studies. The results of this work identify components of the acute-subacute response to closed-head injury and potential biomarkers for assessing TBI.