Neuropathological mRNA Expression Changes after Single Mild Traumatic Brain Injury in Pigs

Abstract

Traumatic brain injury (TBI) is a public health concern, with an estimated 42 million cases globally every year. The majority of TBIs are mild TBIs, also known as concussion, and result from the application of mechanical forces on the head. Most patients make a complete recovery and mortality is rare; therefore, studies investigating cellular changes after mild TBI in a clinical setting are limited. To address this constraint, our group utilized a pig model of closed-head rotational acceleration-induced TBI, which recreated the biomechanical loading parameters associated with concussion on a large gyrencephalic brain similar to humans. While our previous research has focused on immunohistochemical characterization of neuropathology, the current study utilized transcriptomic assays to evaluate an array of TBI-induced neurodegenerative analytes. Pigs subjected to mild TBI were survived for 3 days post-injury (DPI) (n = 3), 30 DPI (n = 3), or 1 year post-injury (YPI) (n = 3) and compared to animals undergoing a sham procedure (n = 8). RNA was isolated from whole coronal sections of fixed tissue and multiplexed on a Nanostring neuropathology panel. Differential expression analysis revealed 11 differentially expressed genes at 3 DPI versus sham, including downregulation of the synaptotagmin calcium sensor gene (SYT1), upregulation of the neurofibromin gene (NF1), and upregulation of the Alzheimer’s disease-associated receptor gene (SORL1). There were no differentially expressed genes at 30 DPI or 1 YPI compared to shams. Additionally, high-magnitude undirected global significance scores (GSS) were detected at 3 DPI for chromatin modification and autophagy gene sets, and at 30 DPI for cytokine gene sets, while many dysregulated gene sets were highlighted by directed GSSs out to 1 YPI. This study adds to a growing body of literature on transcriptomic changes in a clinically relevant large animal model of closed-head TBI, which highlights potential therapeutic targets following mild TBI.