Sex and Genotype Affect Mouse Hippocampal Gene Expression in Response to Blast-Induced Traumatic Brain Injury

Blast-induced traumatic brain injury (bTBI) has been identified as an increasingly prevalent cause of morbidity and mortality in both military and civilian populations over the past few decades. Functional outcomes following bTBI vary widely among individuals, and chronic neurodegenerative effects including cognitive impairments can develop without effective diagnosis and treatment. Genetic predispositions and sex differences may affect gene expression changes in response to bTBI and influence an individual's probability of sustaining long-term damage or exhibiting resilience and tissue repair. Male and female mice from eight genetically diverse and distinct strains (129S1/SvImJ, A/J, C57BL/6J, CAST/EiJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, WSB/EiJ) which encompassed 90% of the genetic variability in commercially available laboratory mice were exposed to a single bTBI (180 kPa) using a well-established shock tube system. Subacute changes in hippocampal gene expression due to blast exposure were assessed using RNA-seq at 1-month post-injury. We identified patterns of dysregulation in gene ontology terms and canonical pathways related to mitochondrial function, ribosomal structure, synaptic plasticity, protein degradation, and intracellular signaling that varied by sex and/or strain, including significant changes in genes encoding respiratory complex I of the electron transport chain in male WSB/EiJ mice and the glutamatergic synapse across more than half of our groups. This study represents a multi-level examination of how genetic variability may influence response to bTBI and provides a foundation for the identification of potential therapeutic targets that could be modulated to improve the health of Veterans and others with histories of blast exposures.