Progressive transcriptional changes in amygdala implicate neuroinflammation in the effects of repetitive low-level blast exposure in rats.

Chronic mental health problems are common among military veterans who suffered blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns with most DEGs unique to one condition. Six DEGs (Hapln1, Grm2, P2ry12, Ccr5, Pbld1 and Cdh23) were found in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast vs. sham. In particular, amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor α (TNFα) signaling in blast-related effects in amygdala and anterior cortex. EIF4e, an upstream regulator of P2ry12 and Ccr5 was predicted to be activated in amygdala. qPCR validated longitudinal changes in two TNFα regulated genes (Ctsb, Hapln1), P2ry12 and Grm2. These studies have important implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

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