Retinal microgliosis, functional sequelae, and traumatic brain injury (TBI) in an impact concussion mouse model.

Abstract

Purpose : Head trauma is a potent stimulus for brain inflammation, a neurotrauma hallmark that is characterized by reactive microgliosis, infiltration of peripheral monocytes, and pro- and anti-inflammatory molecules. These responses can either facilitate recovery or trigger sequelae. Activation and interaction of specific immune cells and phenotypes are determinative of temporal pacing and outcome of brain recovery after concussive head injury.

Methods : We utilized Ccr2RFP/Cx3cr1GFP mice (Jackson Laboratory) to enable immune cell visualization by class (microglia, monocyte), origin (peripheral, brain, retina), morphology, and location. We used a new closed-head impact injury mouse model (Tagge et al., submitted) that recapitulates key features of human concussion. Experimental injury was conducted without anesthesia (approved IACUC protocol) to enable quantitative neurological assessment (Boston University Concussion Scale, BUCS; ibid.). We evaluated histopathology, ultrastructural analysis, blood-brain/retinal barrier function, immune cell imaging, and electrophysiology. We also used an adaptive optics fluorescence scanning laser ophthalmoscope (AO-fSLO) with OCT imaging (Physical Sciences, Inc.) and electroretinography (ERG).

Results : Head-injured mice exhibited transient contralateral hemiparesis, truncal ataxia, impaired balance, and abnormal locomotion that recapitulated concussion in humans. Impact injury induced axonopathy, blood-brain barrier disruption, reactive astrocytosis and microgliosis, and peripheral monocyte infiltration. Concussive signs did not correlate with structural endpoints. Before injury, Ccr2RFP/Cx3cr1GFP mice showed normal cellular distribution and morphological phenotype of resting microglia in retina and brain. We observed significant increase in microglia in retina and brain post-injury. Microgliosis included reactive phenotype transformation with overlapping ramifications and perivascular changes. ERG analysis (see Akula et al.) showed attenuated photoreceptor, postreceptor, and inner retinal responses after head injury.

Conclusions : Closed-head impact injury is associated with reactive inflammatory responses and sequelae in both retina and brain. The retina can be used as a “brain proxy” for noninvasive diagnosis, prognosis, staging and monitoring of neuroinflammation after closed-head injuries.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.