Abstract
Penetrating traumatic brain injuries, often caused by projectiles like shrapnel, have become increasingly common in modern warfare. These injuries have high mortality rates and can lead to severe, long-term neurological deficits. The hippocampus is composed of distinct subregions with unique transcriptomic profiles and cytoarchitecture, and its dysfunction after TBI is closely linked to neurological sequelae, including cognitive and memory impairments. While previous research has explored general brain responses to TBI, the specific molecular changes in individual hippocampal subregions in TBI remain poorly understood. To address this, we used laser-capture microdissection, RNA-sequencing, and differential gene expression matched with gene ontology analysis to investigate transcriptional responses in hippocampal subregions (CA1, CA2, CA3, and dentate gyrus) following high-velocity penetrating TBI in a rat model. Our findings reveal distinct gene expression patterns in each region, reflecting varied pathophysiological responses. CA1 exhibited increased expression of cell-cycle and gliogenesis-associated genes, indicating cytoskeletal stress and gliogenesis-associated signaling. CA2 showed strong immune activation, highlighting leukocyte signaling, MHC antigen processing, and complement pathways, coupled with downregulation of oxidative phosphorylation, suggesting immune-driven metabolic dysfunction. CA3 displayed a pronounced inflammatory profile, marked by TNF signaling and adhesion remodeling. In contrast, the dentate gyrus upregulated genes linked to tissue repair, including ECM stabilization and angiogenesis, suggesting a neuroprotective response. These results highlight the complex, subregion-specific balance between injury and repair mechanisms following TBI, with the hippocampus likely contributing to injury progression through its widespread neuronal connections. Understanding these molecular dynamics is essential for developing targeted interventions aimed at mitigating damage and promoting recovery, especially in the context of increasing high-velocity brain injuries due to modern conflict.