Traumatic brain injury (TBI) is one of the most devastating and costly forms of trauma dealt with in our society. The high level of behavioral morbidity after TBI has been associated with acute episodes of generalized neuroexcitation and diffuse axonal injury, in addition to other forms of focal change. These issues are not easily addressed in many of the established animal models of brain injury, which generally produce excitotoxicity without significant axotomy or target deafferentation. In order to better address these issues, we have developed a new rat model of TBI which combines excitotoxicity and deafferentation. In this model fluid percussion TBI is followed 24 hours later by entorhinal cortical lesion (EC lesion), a well established injury which produces focal deafferentation in the rat hippocampus. The objective of the present project is to use this rat combined insult model to investigate how neuroexcitation and focal deafferentation interact to produce some of the devastating pathobiology of human TBI. Further, the goal includes testing manipulations of each injury component of the combined insult model in order to improve the efficacy of therapy. We will initially determine the extent and duration of motor and spatial memory deficits following the combined insult. At time intervals showing the greatest behavioral change postinjury, we will evaluate the capacity to induced long term potentiation (LTP) in hippocampal CA1 neurons and assay for alterations in protein kinase C (PKC) in dissected hippocampal subregions. Using light and electron microscopy we will also examine the morphological patterns of synaptic remodeling in the combined insult model and establish the postinjury intervals where synaptic change is most pronounced. LTP will again be evaluated at times of synaptic remodeling and further physiological examination will include changes in ongoing firing rate at select postinjury intervals. Src TK and ras G- protein will be assayed to determine if the combined insult affects signal transducers active during sprouting and synapse reformation. Finally, we will test the affect of blocking both muscarinic and glutaminergic induced excitotoxicity of TBI on the behavioral outcome following combined insult. These studies will provide new and useful information, not available with existing animal models, regarding the physiological, morphological and molecular events that may contribute to initial morbidity and less than optimal long term recovery seen with human TBI. Manipulation of these events may then provide a means for better treatment of TBI patients.
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