Development and Characterization of a Novel Mouse Model of Single and Repetitive Mild Traumatic Brain Injury

Mouzon, Benoit Christian (2013). Development and Characterization of a Novel Mouse Model of Single and Repetitive Mild Traumatic Brain Injury. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f034

Abstract

Mild traumatic brain injury (mTBI) or concussion is the most common form of TBI, and although a single concussion rarely results in long-term neurological dysfunction, repeated mild traumatic brain injury (r-mTBI) is a recognized risk factor for later development of neurodegenerative disease. However, the mechanisms contributing to neurodegeneration following TBI remain obscure. Animal models provide a means to examine the factors and mechanisms involved in TBI in experiments that cannot be conducted using human participants.

The purpose of this thesis was to develop and fully characterize a reproducible, non-invasive mTBI model that will facilitate the study of repetitive brain injury. In the present study, male wild type mice received a midline concussive blow via an electromagnetic impactor, tuned to produce an injury without fracturing the skull. The injured mice were used to examine the chronic neurobehavioral, neuropathological and biochemical outcomes following single and r-mTBI up to 18 months following injury. Importantly, our findings recapitulate many aspects of human long term TBI sequelae, in particular persistent neuroinflammation, white matter injury, and axonal pathology in the corpus callosum. Our results provide the first evidence that, whilst a single concussion produces transient neurobehavioral changes and pathology which remains static in the period following injury, r-mTBI produces behavioral and pathological changes which continue to evolve many months post injury.

There have been a number of clinical studies implicating tau in TBI pathology. As such, we investigated the relationship between tau pathologies after trauma in a transgenic mouse model expressing all 6 isoforms of human tau protein on a null murine background (hTau). Our results revealed that that single and r-mTBI induced a modest cortical increase in the soluble fraction of three different p-tau epitopes at 24 h post last injury. Moreover, this increase was not associated with worse behavioral performance when compared to wild type animals. Therefore, tau hyperphosphorylation appears to have a contributory, but not primary, role in the acute phase post-injury. Additional prospective studies in both humans and animal models are required to characterize the contribution of tau to TBI sequelae.

The experimental data presented here suggest that inflammation and axonal injury (as seen in both wild-type and hTau models) appear to play a role in the events following single or repetitive mTBI and strongly correlates with the behavioral changes post-injury. The relationship between a history of mTBI and neuroinflammation are likely to be complex and warrant further work to elucidate their association with neurodegenerative disease. This work represents the development of a novel model, and the demonstration of its relevance to human TBI. This model can now be used for further exploration of TBI-related effects and for evaluation of potential therapeutic and diagnostic approaches, as is discussed throughout the thesis.