In Vivo Retinal Imaging of Post-Traumatic Neuroinflammation and Sequelae in Impact Concussion and Blast Exposure Mouse Models

Abstract

Purpose : Impact and blast neurotrauma induce post-traumatic microvasculopathy and neuroinflammation in brain and retina. Activation and interaction of specific immune cells are determinative of pacing and outcome post-injury. We investigated retinal cell imaging as a novel in vivo diagnostic technique for neuroaxis evaluation post-injury. We used new mouse models that recapitulate key features of acute concussion, mild traumatic brain injury (mTBI), and chronic traumatic encephalopathy (CTE) in humans.

Methods : Ccr2RFP/Cx3cr1GFP mice (Jackson Laboratory) enabled immune cell visualization by class (microglia, monocyte), origin (brain, retina, periphery), morphology, and location. Mouse models (matched for head kinematics): (i) closed-head impact injury (Tagge et al., Brain, 2018), (ii) blast exposure (Goldstein et al., Science Transl Med, 2012; Kondo et al., Nature, 2015). Mice were not anesthetized to enable acute neurobehavioral testing (Boston University Concussion Scale, BUCS). TBI-CTE histopathology, ultrastructure (EM), blood-brain/blood-retinal barrier function, immune cell imaging, electroretinography (ERG). Adaptive optics fluorescence scanning laser ophthalmoscope (AO-fSLO) with OCT imaging (Physical Sciences, Inc.).

Results : Impact-injured mice showed transient neurological impairment (contralateral hemiparesis, truncal ataxia, abnormal gait-balance), whereas blast-exposed mice did not. However, both experimental injuries induced axonopathy, microvasculopathy, monocyte infiltration, astrocytosis, microgliosis, and tau proteinopathy. BUCS scores did not correlate with structural, pathological, or functional endpoints. Before injury, Ccr2RFP/Cx3cr1GFP mice showed normal microglial distribution and phenotype in retina and brain. We detected focal microgliosis by in vivo retinal imaging that correlated with post-traumatic brain pathology. ERG analysis showed attenuated photoreceptor, postreceptor, and inner retinal responses post-injury.

Conclusions : Impact and blast neurotrauma induce distinct acute neurological responses but similar patterns of neuroinflammation, microvasculopathy, and functional sequelae in retina and brain. These results suggest that retinal cell imaging may be useful for noninvasive diagnosis, prognosis, staging, and monitoring of neurotrauma-related pathologies post-injury. Correlation with long-term TBI-CTE sequelae is underway.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.