FOCAL CEREBRAL ISCHEMIA--PATHOPHYSIOLOGY, ACUTE THERAPY, RECOVERY OF FUNCTION

局灶性脑梗死后最初几小时内的生化和离子事件 血管闭塞决定了细胞的范围和强度 死亡，并可能提供关键的刺激，以随后的功能 大脑的重组和恢复。该项目采用了 广泛表征的微创光血栓模型 大脑中动脉（MCA）闭塞-一种与人类相关的模型 血栓栓塞性中风一个主要目的是表征因素 负责产生急性生物能应激的缺血 半暗带，包括过度局部代谢/血流解耦， 反复出现缺血性去极化这些过程之间的关系 谷氨酸和其他神经递质的局部释放， 氧自由基的本地生产，将被探索。分析 局部细胞骨架蛋白水解和光镜和电镜 组织病理学将提供结构相关性。调节急性 半影区的代谢事件将通过诱导额外的 去极化，轻度高温或低温，早期部分 再灌注，以及影响谷氨酸系统的药物。第二 主要目的是确定这些急性事件如何影响随后的 功能恢复模式，通过神经行为评估 电池，通过受影响前肢区域的葡萄糖代谢活化，以及 通过表达神经营养因子生长的信使RNA和蛋白质 因子及其TRK受体。我们将辨别是否急性 保护性策略可能有助于或矛盾地阻碍后来的功能性 重组，我们将评估的机制， 安非他明结合症状- 相关经验。该项目广泛使用了三种新的- 三维放射自显影图像平均策略结合 用神经行为学、原位杂交、免疫组织化学和 形态学方法

Biochemical and ionic events within the first few hours after focal vascular occlusion critically determine the extent and intensity of cell death and may provide critical stimuli to subsequent functional rearrangement and recovery of the brain. This project employs an extensively characterized, minimally invasive model of photothrombotic middle cerebral artery (MCA) occlusion -a model relevant to human thromboembolic stroke. A major aim is to characterize factors responsible for engendering acute bioenergetic stress in the ischemic penumbra, including excessive local metabolism/blood flow uncoupling and repeated ischemic depolarizations. The relationship of these processes to the local release of glutamate and other neurotransmitters, and to the local production of oxygen radicals, will be explored. Analysis of local cytoskeletal proteolysis and light- and electron microscopic histopathology will provide structural correlates. Modulation of acute metabolic events in the penumbra will be achieved by inducing additional depolarizations, by mild hyperthermia or hypothermia, by early partial reperfusion, and by agents affecting the glutamate system. The second major aim is to determine how these acute events influence subsequent patterns of functional recovery, as assessed by a neurobehavioral battery, by glucose-metabolic activation of affected forelimb areas, and by the expression of messenger RNA and protein for neurotrophin growth factors and their trk receptors. We shall discern whether acute protective strategies might aid or paradoxically hinder later functional reorganization, and we shall assess the mechanisms underlying the enhancement of functional recovery by amphetamine coupled with symptom- relevant experience. The project makes extensive use of novel three- dimensional autoradiographic image-averaging strategies in conjunction with neurobehavior, in situ hybridization, immunohistochemistry and morphologic methods.