In this paper, we investigate the potential for the development of a composite score investigating population-level phenotype changes in a mouse model of traumatic brain injury. Traumatic brain injuries (TBI) are a growing concern in the United States because the number of individuals impacted by TBI and associated symptoms is increasing, leading to a growing demand for research both in the clinical and preclinical setting. However, preclinical TBI modeling is complicated by the lack of inter and intra lab consistency in the assessment of behavioral and pathologic outcomes. Indeed, it remains unclear which behavior assessments are most useful in evaluating the effects of preclinical TBI. To investigate the relative contribution of various behavior tests in the assessment of preclinical TBI, three statistical models (simple linear regression, pairwise correlation, and factor analysis) were conducted on behavioral data from the Mannix-Meehan lab at Boston Children’s Hospital in Boston, Massachusetts, U.S.A. from 2012-2018. In this paper, a composite metric was created from the computation analysis of the three statistical methods. The score revealed MWM and EPM as the most potent behavioral tests. The Open Field and Rotarod test had a small impact on the outcome, but only in one of the three statistical models assessed. Thus, to effectively analyze treatment efficiencies, injury severity and long-term impairments, MWM and EPM are the best behavioral test for a mouse model. Furthermore, this method of analysis of entire populations of mice allows for more subtle phenotypic changes resultant from injury models to be revealed, and the generalizability of this model lends to widespread use.

abstract: Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for 70-90% of all TBI cases, yet its neuropathophysiology is still poorly understood. While a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (post-natal day 20) to repeat weight drop impact. Animals were anesthetized and subjected to sham or rmTBI once per day for 5 days. At 14 days post injury (PID), magnetic resonance imaging (MRI) revealed that rmTBI animals displayed marked cortical atrophy and ventriculomegaly. Specifically, the thickness of the cortex was reduced up to 46% beneath and the ventricles increased up to 970% beneath the impact zone. Immunostaining with the neuron specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker, 4-Aminophyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents. / Dissertation/Thesis / Masters Thesis Biology 2014