Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury

Abstract

Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to Alzheimer’s disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority.

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

“…19,20,[22][23][24][25][26]28,[30][31][32][33][128][129][130][131][132][133] These approaches avoid the severe focal contusive brain injury associated with open-skull TBI models, while a single exposure, depending on the blast pressure, can yield axonal injury, microglial activation, edema, and cognitive, emotional, and visual deficits, 20,23,24,26,28,30,31,33,[128][129][130][131]133,134 similar to those observed with our focal blast model. For example, significant rotarod motor deficits and axonal swellings have been reported for 2 weeks after a whole body 15-psi blast in mice, 19,24 and hippocampal neuron loss has been reported in rats 2 weeks after whole body 18-psi blast.…”

“…35,[37][38][39][133][134][135][136]138,139,[141][142][143][144][145][146][147][148] For example, rotarod deficits and axon injury have been reported after weightdrop TBI. 141,149 A more detailed review of functional deficits and brain pathology after TBI created by impact or weight drop on a closed skull has been provided by others.…”

Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

“…Hippocampal gene expression profiles were compared between mTBI and sham animal samples, as has been described previously (Tweedie et al, 2013a,b; 2015). Raw array chip hybridization image signals were filtered and processed to generate normalized data that was then transformed to create Z-scores for each gene.…”

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

“…10,11,14,21,22 However, even low-level blast pressure waves are transmitted to the brain and exert a variety of biochemical, pathological, and physiological effects in animals, including the induction of chronic behavioral effects. 3,10,14,[21][22][23][24][25][26][27][28][29] Modulation of gene expression mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, is one way the brain creates new homeostasis in response to experience, including response to injury. 30 Aberrant regulation of gene expression contributes to long-lasting behavioral abnormalities, where epigenetic modifications serve as a regulatory layer decoding environmental signals into sustained changes in gene expression.…”