Focal and diffuse impacts of mild vs. moderate traumatic brain injury (TBI): Temporal assay of hippocampal and cerebellar transcriptomics

Abstract

Traumatic brain injury (TBI) results in a complex of physiological and psychological deficits. The study described here utilizes a closed‐head injury Marmarou model. The injuries were caused by the release of a 500 gram steel slug on top of the rat skull between lambda and bregma from a height of 100 cm (to induce mild TBI) or 120 cm (to induce moderate TBI). The focal injury at the point of impact of a steel slug triggers a diffuse secondary‐injury cascade. These focal‐to‐diffuse injuries are known to negatively affect a wide range of cerebral functions that involve multiple brain regions. Here, we sought to contrast the molecular and functional dynamics of two brain regions; one is located at the focal point of injury and other one is located at distal site from the focal injury. The hippocampus is at the focal injury and the cerebellum, although distally removed from the injury site, is within the range of receiving the diffused shock (secondary injury). The Barnes Maze behavioral assays were used to assess the efficacy of processing the retained memories and visuomotor integration in these two regions. The Barnes Maze was performed for five consecutive days starting 14 days post‐injury. A significant delay in latency, defined as learning response to a novel spatial challenge, following mild TBI as compared to pre‐TBI was sustained until the third test day. In moderate TBI, the delay in latency remained significant until the fourth day of maze testing, and the significance declined to a p value = 0.08 on the last day of maze testing.Transcriptomic changes in the hippocampus and cerebellum paralleled the focal‐to‐diffuse responses to TBI. Interestingly, a very different set of genes were significantly perturbed in the hippocampus and cerebellum injured by mild vs. moderate TBI. The underlying differences between the focal‐to‐diffuse TBI responses were further highlighted by downstream functional network analyses. Networks linked to cellular functions remained inhibited, and networks linked to skin cell death remained activated in the hippocampus in moderate TBI 14 days post‐injury.In conclusion, we observed networks that can potentially discriminate mild TBI from moderate TBI and this indicated the role of the hippocampal‐cerebellar interaction in response to TBI. These results reinforce the values of carrying out knowledge‐driven categorization assays to stratify the extent of injuries caused by graded TBI models.Disclaimer: Research was conducted in compliance with the Animal Welfare Act, and all other Federal requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.Support or Funding InformationFunding support from Military Operational Medicine Research Program, MOMRP is highly acknowledged.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.