RECEPTOR MEDIATED NEUROEXCITOTOXICITY/SELECT DEAFFERENTATION FOLLOWING TBI

创伤性脑损伤（TBI）是最具破坏性和成本最高的 在我们的社会中处理创伤的形式。 高水平的行为 TBI后的发病率与以下急性发作相关： 全身性神经兴奋和弥漫性轴索损伤，此外， 其他形式的焦点变化。 这些问题不容易解决， 许多已建立的脑损伤动物模型， 产生兴奋性毒性，无明显轴突切断或靶点 传入神经阻滞为了更好地解决这些问题，我们 开发了一种新的大鼠TBI模型，该模型结合了兴奋性毒性和 传入神经阻滞 在该模型中，流体冲击TBI被跟踪24小时 后来通过内嗅皮层病变（EC病变），一个良好的建立 在大鼠海马中产生局灶性传入神经阻滞的损伤。 的 本项目的目的是使用这种大鼠联合损伤模型 研究神经兴奋和局灶性传入阻滞如何相互作用， 产生了一些人类创伤性脑损伤的毁灭性病理学。 此夕h 目标包括测试操作的每一个伤害组成部分， 联合损伤模型，以提高治疗效果。 我们 将最初决定运动和空间的程度和持续时间 记忆力减退 每隔一段时间 最大的行为变化，我们将评估 诱导海马CA 1区神经元长时程增强（LTP）， 分离的海马中蛋白激酶C（PKC）的改变的测定 分区域. 使用光学和电子显微镜，我们还将检查 联合损伤中突触重塑的形态学模式 建立损伤后突触变化的时间间隔， 最明显的。 LTP将在突触时再次评估。 重塑和进一步的生理检查将包括 持续的放电频率。 Src TK和ras G- 将测定蛋白质以确定组合的损伤是否影响 信号传导器在发芽和突触重组期间活跃。 最后，我们将测试阻断毒蕈碱和 多巴胺能神经兴奋性毒性对脑外伤后行为学的影响 在联合侮辱之后。 这些研究将提供新的和有用的 现有动物模型无法获得的信息， 生理学、形态学和分子学事件， 初始发病率和低于最佳的长期恢复， 人创伤性脑损伤对这些事件的操纵可能会提供一种手段， 更好地治疗TBI患者。

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.