Traumatic Brain Injury (TBI) is caused by a mechanical insult to the head and often results in prolonged or permanent brain dysfunction. TBI represents a major health and socioeconomic problem; in the U.S. over 2.4 million are affected annually, including over 50,000 deaths, with over 5 million total survivors exhibiting chronic deficits. Even so-called ?mild? TBI ? otherwise known as concussion ? may induce neurophysiological deficits affecting learning, memory, and concentration that do not resolve in up to 15-20% of patients. There are currently no approved treatments to improve recovery from TBI. This proposal will investigate the role of baseline neuroinflammation as a major driver of chronic neurodegeneration following mild TBI. Specifically, we will assess how ongoing neuroinflammatory responses resulting from an initial TBI serve to exacerbate and accelerate chronic neurodegeneration following trauma. Previous extensive neuropathological examinations have shown that mild TBI is associated with subtle changes in synaptic loss or gain and neuronal hypertrophy occurring concomitantly with migration and activation of microglia ? the resident immune cell of the central nervous system. Therefore, our overarching hypothesis is that neuronal dystrophy, inflammation, and synaptic protein changes will occur and that neuroinflammatory and neurodegenerative gene expression will increase in the hippocampus and cortex after TBI. We will evaluate this relationship utilizing archival TBI tissue of over 100 specimens from a unique porcine model. Our porcine model of TBI is the most clinically relevant model of closed-head diffuse TBI in use today, as this model closely replicates human head injury biomechanics that cannot be reproduced in small animals. Additionally, swine possess important neuroanatomical similarities to humans: a relatively large brain mass with gyrencephalic architecture and substantial white matter domains.
In Aim 1, brain tissue from swine survived out to 1 year post-injury will be assessed for neuroinflammatory and neurodegenerative markers in the CA3 and CA1 subregions of the hippocampus using immunohistochemistry and gene expression assays.
In Aim 2, the same tissue will be assessed for neuroinflammatory and neurodegenerative markers in the cerebral cortex using immunohistochemistry and gene expression assays. The proposed studies will profoundly increase our understanding of the chronic neuropathological consequences of a single mild TBI. Our studies will be able to examine gene expression changes at acute to chronic time points and directly relate these contributing molecular factors to mild TBI histopathology in a uniquely translational large animal model. This work will guide future studies by identifying therapeutic target pathways in animal models that may translate to potential treatment for humans. Overall, the current proposal is a critical step in identifying degenerative pathology that underlies the cognitive, behavioral, and motor dysfunctions that millions of Americans experience as a result of TBI each year.
This proposal will investigate the role of neuroinflammation as a major driver of chronic neurodegeneration following mild traumatic brain injury (TBI) ? which affects over 5 million people in the U.S. - as we will evaluate this relationship using archival tissue of over 100 specimens from a unique swine model of clinically relevant TBI to assess neuron loss, inflammation, and synaptic protein changes in the hippocampus and cortex using immunohistochemistry and gene expression assays. We will be able to examine gene expression changes at acute to chronic time points and relate these contributing molecular factors to the chronic neuropathological consequences of mild TBI pathology. This work will guide future studies by identifying therapeutic target pathways in animal models that may translate to potential treatment for humans and is a critical step in identifying degenerative pathology that underlies the cognitive, behavioral, and motor dysfunctions that millions of Americans experience as a result of TBI each year.
