A Spatial Gene Expression Signature of the Mouse Brain Post-Injury at the Focal Point of Contusion.

Abstract

Traumatic brain injury (TBI) results from a primary injury that impacts the brain in a spatially dependent manner. In this study, we investigated the topographical relationship of early transcriptional responses to a single, focal TBI in mice by controlled cortical impact. Guided by the presence of the anterior commissure (AC) in coronal sections at the rostro-caudal point of impact, we compared gene expression changes in the neocortex (CTX) and corpus callosum-external capsule (CC-EC), striatum (STR), and AC. Injury-induced gene expression changes were detected in the CTX, CC-EC, and STR but not AC and were principally segregated based on cytoarchitecture and secondarily by proximity to the site of impact. In addition, unbiased spatial clustering revealed a positive relationship between proximity to the impact and the number of acutely differentially expressed genes within the laminar CTX. Gene pathways for interferon gamma response and for leukocyte-mediated migration and immunity were acutely enhanced across the injured CTX, CC-EC, and STR. Within 1 week post-injury, transcriptional responses to injury in the CTX and CC-EC included gene pathways for adaptive T- and B cell mediated immunity, whereas gene expression changes in the STR were largely resolved. Next, we examined the effects of systemic depletion of neutrophils and monocytes on spatial gene expression changes in the injured brain. The systemic depletion and attenuated infiltration of these immune cells into the damaged brain post-injury led to the upregulation of gene pathways functioning in synaptic transmission and an alternating down- and then upregulation of genes functioning in ribosomal messenger RNA translation and aerobic metabolism in mitochondria. These data suggest that infiltrating neutrophils and monocytes play an evolving, multifaceted role in modulating the metabolic, transcriptional, and synaptic activity of brain tissue post-injury.