Characterization of Neuropathology and Neuroinflammatory Cascades after Mild Traumatic Brain Injury in Swine
Authors:   , Grovola Michael Ross , Cullen D. Kacy , von Reyn Catherine R. 
Published: September 2021

Traumatic Brain Injury (TBI) often results in prolonged or permanent brain dysfunction with over 2.8 million affected annually in the U.S., including over 56,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Mild TBI (also known as concussion) accounts for over 75% of all TBIs every year. Mild TBI is a heterogeneous disorder, and long-term outcomes are dependent on the type and severity of the initial physical event and compounded by secondary pathophysiological consequences such as neuroinflammation, reactive astrocytosis, edema, hypoxia, and excitotoxicity. Neuroinflammation has gained increasing attention for its role in secondary TBI injury as it can have both detrimental and beneficial roles. For example, microglia - the resident immune cell of the central nervous system (CNS) - mediate cell death and may contribute to progressive neurodegeneration but also aid in debris clearance and regeneration. However, prior to the following work microglia had not been studied after diffuse mild TBI in a clinically relevant large animal model at chronic time points. Replicating the injury biomechanics of human mild TBI in animal models presents a substantial challenge, particularly with regards to addressing brain size, neuroanatomy, and acceleration parameters. To address this challenge, our lab uses a swine model of diffuse closed-head TBI that accurately replicates human mild TBI mechanisms and manifestations due to the neuroanatomical similarities between humans and pigs (large gyrencephalic brains with high white to grey matter ratios) that are not present in small animals. This well-characterized model subjects the head to rapid angular acceleration, inducing inertial forces common in human TBI resulting from falls, collisions, or blunt impacts. This injury model has been shown to produce acute and chronic pathologies in patterns that mirror those seen in humans. Therefore, using this rotation-acceleration model of closed-head TBI in pigs, the goal of the studies reported herein was to elucidate the role of microglia and the neuroinflammatory response to single mild TBI out to 1 year post injury through in-depth histological profiling in discrete neuroanatomical regions across three specific aims. First, we assessed the relationship between the hallmark axonal pathology of diffuse TBI and alterations in glial cell activation or morphology. Then, we examined neuroinflammatory and synaptic changes in sub-regions of the dentate gyrus following a single mild TBI, as the hippocampus is notably susceptible to damage post-TBI and microglia may play a role in synaptic remodeling. Finally, we assessed gray matter neuropathology and neuroinflammation in response to a novel mechanism of immediate neuronal membrane disruption following TBI. These studies will inform future work to characterize the underlying molecular and neurophysiological alterations post-TBI, as well as potential contributions to neurological deficits. It is hoped that these aims will translate to advances in the treatment and prevention of the long-term consequences of TBI in people.