PERINATAL HYPOXIA/ISCHEMIA MODEL OF MR AND EPILEPSY

由于缺氧/缺血引起的围产期脑病可导致永久性 神经功能缺陷，如智力迟钝、癫痫和脑 麻痹 围产期缺氧/缺血常常并发急性缺氧/缺血。 癫痫发作 该研究项目的长期目标是：1）使用 动物模型，以确定急性癫痫发作活动如何与长期 术语神经行为缺陷，和2）以确定成熟的 短期和长期癫痫发生的潜在机制， 可以设计针对年龄的预防性疗法。 在体内大鼠中， 围产期缺氧模型，一个惊人的发现是，缺氧导致 脑电图（EEG）和行为癫痫发作的未成年大鼠，但没有 在成人中。在围产期缺氧的大鼠表现出 增加长期癫痫易感性。 没有长期影响 缺氧后癫痫发作。 发展的窗口 缺氧的急性和长期致痫性均介于 大鼠出生后5-17天（P）。 以确定癫痫发作的程度 围产期急性缺氧时的活动影响长期 结果，大鼠表现出不同程度的癫痫样活动， 缺氧将被跟踪到成年期。 氟哌酸诱发癫痫发作 这些成年大鼠的易感性将与它们的行为相关 在围产期缺氧的时候。 为了确定大脑中哪些部位 主要参与缺氧诱导的癫痫发作的产生， 对早期反应基因c-fos的蛋白产物的免疫反应性， 将被用作功能地图。 相对免疫反应性 将新皮层区域与边缘结构的区域进行比较， 包括海马。 因为有证据表明， 缺氧诱导癫痫发作发生是兴奋机制可能 优于那些是抑制性的，兴奋性的功效 氨基酸（EAA）拮抗剂将与劳拉西泮进行比较，劳拉西泮是一种 抑制的促进者，因为他们能够抑制急性 缺氧引起的癫痫发作和长期后果。 海马和 新皮层脑切片将在体外研究， 缺氧的未成熟大鼠，以检查这些结构在隔离， 先天性癫痫样活动的证据 这些体外实验 允许对单个大脑区域进行研究，这是不可能的， 在体内，传入连接可能会改变自发和诱发 神经元活动 动物将在体内接受药物治疗， 缺氧，缺氧后将切片取出，以确定是否在 体外活性揭示了与体内药物的特定区域相关性 功效 总体目标是利用这些体内和体外模型 系统一起确定成熟的因素负责 在整个动物中观察到的独特反应，它们的底层 可以研究分子、生理和生化机制。

Perinatal encephalopathy due to hypoxia/ischemia can result in permanent neurologic deficits such as mental retardation, epilepsy and cerebral palsy. Perinatal hypoxia/ischemia is frequently complicated by acute seizures. The long term goals of this research program are 1) to use animal models to define how the acute seizure activity relates to long term neurobehavioral deficits, and 2) to determine the maturational mechanisms underlying the short and long term epileptogenesis so that age-specific preventative therapies can be devised. In an in vivo rat model of perinatal hypoxia, a striking finding is that hypoxia results in electrographic (EEG) and behavioral seizures in the immature rat, but not in the adult. Rats rendered hypoxic in the perinatal period exhibit increased long term seizure susceptibility. There is no long term effect on seizures after hypoxia at adult ages. The window of development for both the acute and long term epileptogenicity of hypoxia is between postnatal days (P) 5-17 in the rat. To determine if the level of seizure activity during acute hypoxia in the perinatal period affects long term outcome, rats exhibiting varying levels of epileptiform activity during hypoxia will be followed to adulthood. Flurothyl induced seizure susceptibility of these adult rats will be correlated to their behavior during perinatal hypoxia. To identify sites in the brain which are predominantly involved in the generation of hypoxia induced seizures, immunoreactivity to the protein product of an early response gene, c-fos, will be used as a functional map. Relative immunoreactivity in neocortical regions will be compared to that of limbic structures, including the hippocampus, in immature animals sacrificed after hypoxia. Since evidence suggests that the window of development during which hypoxia-induced seizures occur is a period when excitatory mechanisms may predominate over those which are inhibitory, the efficacy of excitatory amino acid (EAA) antagonists will be compared to lorazepam, which is a facilitator of inhibition, for their ability to suppress both the acute hypoxia-induced seizures and the long term consequences. Hippocampal and neocortical brain slices will be studied in vitro after removal from hypoxic immature rats to examine these structures in isolation for evidence of inherent epileptiform activity. These in vitro experiments allow the study of individual brain regions, which is not possible in vivo, where afferent connectivity may alter spontaneous and evoked neuronal activity. Animals will be treated with drugs in vivo prior to hypoxia, and slices will be removed after hypoxia to determine if in vitro activity reveals specific regional correlates to in vivo drug efficacy. The overall goal is to use these in vivo and in vitro model systems together to identify maturational factors responsible for the unique responses observed in the whole animal so that. their underlying Molecular, physiological, and biochemical mechanisms may be studied.