BRAIN DEVELOPMENT IN EXPERIMENTAL EPILEPSY

本项目将研究脑损伤的兴奋性毒性机制。 新生儿大脑中的癫痫。我们将开发一种重复的模型 N-甲基-D-天冬氨酸(NMDA)诱导10日龄大鼠癫痫发作。血样 血压、血气和其他生理参数将被监测 并进行纠正，以确定由此造成的脑损伤是否 与癫痫本身或其全身并发症有关。我们 将描述和量化脑损伤的程度，重点是 海马区，将建立剂量和时间曲线，以及年龄依赖关系 癫痫引起的损伤。我们希望找到一个损害的分布在 内层颗粒细胞。损伤的兴奋毒性性质将是 经电子显微镜证实，经NMDA阻滞剂治疗 受体，以及内嗅觉损伤。 我们还将建立未成熟大鼠兴奋性中毒性脑损伤模型。 通过刺激穿孔路径。我们预计最终发布的版本 内源性谷氨酸会损伤内层颗粒细胞 这将被NMDA拮抗剂阻断。我们也 期望不那么强烈的刺激不会引起神经元 坏死会抑制海马区的生长。我们将对此进行研究 星形胶质细胞、髓鞘和各种神经元亚群的特异性标记物 特兹。 在啮齿动物身上获得的关键发现将应用于非人类灵长类动物。 通过建立新生恒河猴穿支通路刺激模型 猴子，测量由此造成的脑损伤，并用NMDA阻断它 对抗者。 我们期望这些研究将大大促进我们对 癫痫发作导致未成熟大脑损伤的机制。

This project will study excitotoxic mechanisms of brain damage induced by seizures in the brain of the neonate. We will develop a model of repetitive seizures induced by N-methyl-D-aspartate (NMDA) in ten-day-old rats. Blood pressure, blood gases and other physiological parameters will be monitored and corrected in order to ascertain whether the resulting brain damage is associated with the seizures themselves or their systemic complications. We will describe and quantify the degree of brain damage with emphasis on the hippocampus, will establish dose and time curves, and the age dependence of seizure-induced damage. We expect to find a distribution of damage in the inner layer granule cells. The excitotoxic nature of the lesions will be confirmed by electron microscopy, by treatment with blockers of the NMDA receptor, and by entorhinal lesions. We will also develop a model of excitotoxic brain damage in immature rats by stimulation of the perforant path. We expect that the resulting release of endogenous glutamate will damage the inner layer granule cells of the dentate gyrus and that this will be blocked by NMDA antagonists. We also expect that less vigorous stimulation which does not cause neuronal necrosis will inhibit hippocampal growth. This will be studied with specific markers for astrocytes, myelin, and various neuronal subpopula- tions. The key findings obtained in rodents will be applied to non-human primates by developing a model of perforant path stimulation in newborn marmoset monkeys, measuring the resulting brain damage, and blocking it with NMDA antagonists. We expect those studies to significantly advance our understanding of the mechanism of damage resulting from seizures in the immature brain.