Transcriptional Pathology Evolves over Time in Rat Hippocampus after Lateral Fluid Percussion Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer an opportunity to study the temporal progression of disease from injury to recovery. Transcriptomic and epigenomic analysis were applied to evaluate gene expression in ipsilateral hippocampus at 1 and 14 days after sham ( n = 2 and 4, respectively per time point) and moderate lateral fluid percussion injury ( n = 4 per time point). This enabled the identification of dynamic changes and differential gene expression (differentially expressed genes; DEGs) modules linked to underlying epigenetic response. We observed acute signatures associated with cell death, astrocytosis, and neurotransmission that largely recovered by 2 weeks. Inflammation and immune signatures segregated into upregulated modules with distinct expression trajectories and functions. Whereas most down-regulated genes recovered by 14 days, two modules with delayed and persistent changes were associated with cholesterol metabolism, amyloid beta clearance, and neurodegeneration. Differential expression was paralleled by changes in histone H3 lysine residue 4 trimethylation at the promoters of DEGs at 1 day post-TBI, with the strongest changes observed for inflammation and immune response genes. These results demonstrate how integrated genomics analysis in the pre-clinical setting has the potential to identify stage-specific biomarkers for injury and/or recovery. Though limited in scope here, our general strategy has the potential to capture pathological signatures over time and evaluate treatment efficacy at the systems level.

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

“…and the up-regulation of pro-inflammatory genes (e.g., Nlrp3 and Tlr4) (Catta-Preta et al, 2021). Altogether, this suggests that changes in cholesterol metabolism after TBI may contribute to persistent neuroinflammation that can promote chronic neurodegeneration.…”

“…In a diffuse injury model in rats (fluid percussion injury), ABCA1 was increased at 10 days post‐injury, but brain cholesterol levels did not correlate with liver pro‐inflammatory markers IL‐1α, IFNγ, TNFα, and MCP‐1 (Palafox‐Sanchez et al, 2021). At later time points, sterol biosynthesis genes were down‐regulated in injured tissue, and were accompanied by down‐regulation of microglial immunoregulatory genes (e.g., P2ry12 ) and the up‐regulation of pro‐inflammatory genes (e.g., Nlrp3 and Tlr4 ) (Catta‐Preta et al, 2021). Altogether, this suggests that changes in cholesterol metabolism after TBI may contribute to persistent neuroinflammation that can promote chronic neurodegeneration.…”

Functional recovery following traumatic brain injury in rats is enhanced by oral supplementation with bovine thymus extract

“…[79][80][81][82][83] While not many changes in gene expression were reported between days 14 and 30 after TBI, large numbers of genes appear to remain either up-or downregulated long-term. 79,81 In our study, we find that CCI induces persistent changes in gene expression patterns in Vehicle-CCI animals, with the majority of differentially expressed genes involved in inflammation and tissue repair (Figure 3). Conversely, we find that thymus extract supplementation and TNF supplementation, in particular, induce notably larger changes in hippocampal gene expression patterns compared to Vehicle-CCI group (797 vs. 70 differentially expressed genes for TNF-CCI versus Vehicle-CCI groups, respectively) (Table S1).…”

“…Multiple studies have reported dramatic changes in rat hippocampal gene expression levels following moderateto-severe TBI at both the early, acute timepoints after the injury and throughout the recovery period. [79][80][81][82][83] While not many changes in gene expression were reported between days 14 and 30 after TBI, large numbers of genes appear to remain either up-or downregulated long-term. 79,81 In our study, we find that CCI induces persistent changes in gene expression patterns in Vehicle-CCI animals, with the majority of differentially expressed genes involved in inflammation and tissue repair (Figure 3).…”

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

“…We downloaded two mRNA expression datasets (GSE111452 and GSE173975) from the GEO database (ht tps://www.ncbi.nlm.nih.gov/geo/) [18,19]. In two experiments, adult male Sprague-Dawley (SD) rats were used as the experimental models.…”