RECEPTOR MEDIATED NEUROEXCITOTOXICITY/SELECT DEAFFERENTATION FOLLOWING TBI

创伤性脑损伤是最具破坏性和代价最高的疾病之一。 在我们的社会中处理的各种形式的创伤。高水平的行为 颅脑损伤后的发病率与急性脑损伤的发作有关 全身性神经兴奋和弥漫性轴索损伤 其他形式的焦点改变。这些问题不是很容易在 许多已建立的脑损伤动物模型，通常 在没有明显轴突切开或靶点的情况下产生兴奋毒性 去感觉神经。为了更好地解决这些问题，我们已经 建立了一种新的大鼠脑创伤模型，它结合了兴奋性毒性和 去感觉神经。在该模型中，对液压冲击伤进行24小时的追踪 后来由内嗅觉皮质损害(EC损害)，一个完善的 在大鼠海马区产生局灶性去传入的损伤。这个 本项目的目的是利用这种大鼠联合损伤模型 研究神经兴奋和局灶性去传入如何相互作用 产生一些人类脑损伤的毁灭性的病理生物学。此外， 目标包括测试每个受伤组件的操作 联合侮辱模型，以提高治疗效果。我们 将初步确定运动和空间运动的范围和持续时间 综合侮辱后的记忆缺陷。每隔一段时间显示 受伤后最大的行为变化，我们会评估能力 诱导海马CA1区神经元长时程增强(LTP)和 分离的海马区蛋白激酶C(PKC)变化的检测 子区域。利用光学和电子显微镜，我们还将研究 复合损伤后突触重构的形态变化 建立并建立损伤后突触改变的间期 最明显的。LTP将在突触时再次进行评估 重建和进一步的生理检查将包括 在选定的受伤后时间间隔内的持续射击率。SRC TK和RAS G- 蛋白质将被检测，以确定联合侮辱是否会影响 信号转导在萌发和突触重塑过程中激活。 最后，我们将测试阻断毒扁豆碱和 谷氨酸能兴奋性脑损伤对行为结局的影响 接踵而至的是联合侮辱。这些研究将提供新的有用的 现有动物模型无法获得的信息，关于 生理、形态和分子事件可能有助于 最初的发病率和不太理想的长期恢复 人类脑外伤。然后，对这些事件的操纵可以提供一种手段 更好地治疗颅脑损伤患者。

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.