ISCHEMIA INDUCED NEUROGENESIS AND PLASTICITY

缺血引起的神经发生和可塑性

• 批准号: 6490950
• 负责人: FRANK R SHARP
• 金额: $ 26.02万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6490950
• 关键词: antimetabolites; blocking antibody; calbindin; dentate gyrus; dyes; electron microscopy; erythropoietin; gangliosides; gerbil /jird; granule cell; hippocampus; immunocytochemistry; injection /infusion; ischemia; microtubule associated protein; mossy fiber; nerve /myelin protein; neural plasticity; neurogenesis; stem cells; synapsins; synaptogenesis; western blottings

DESCRIPTION (From Abstract): New cells are born in the brain throughout adult life. One source of newborn cells is the subgranular zone of the dentate gyrus of the hippocampus. The newborn cells have the potential for forming neurons, astrocytes or oligodendrocytes. Many cells born in the subgranular zone that migrate into the granule cell layer form mature neurons. NMDA receptors, seizures and stress hormones regulate this neurogenesis. We have found that ischemia also up-regulates neurogenesis. BrdU immunohistochemistry was used to show a 9-fold increase of cell birth in the dentate subgranular zone 1-2 weeks following global ischemia. The newborn cells in the subgranular zone migrate into the granule cell layer where 60-66% mature into neurons. Some of the cells born in the subgranular zone also migrate into the dentate hilus where 10-20% become astrocytes. The ischemia-induced dentate neurogenesis was not caused by stress of by cell death in entorhinal cortex. The present study is designed to examine the fate of the newborn neurons and to examine the mechanism of ischemic induction of neurogenesis in the rodent brain. It is hypothesized that the neurons born in the dentate following global ischemia: extend axons to the target CA3 pyramidal neurons; up-regulate synaptic proteins; increase the numbers of synapses on CA3 pyramidal neurons; and increase the total number of neurons in the dentate granule cell layer. Experiments will determine: whether retrogradely transported dyes injected into the CA3 zone of hippocampus co-localize with BrdU labeled nuclei and the NeuN, MAP-2 and calbindin neuronal markers in the dentate granule cell layer following global ischemia; Whether pre-synaptic proteins are up-regulated following global ischemia in the newborn neurons and in the CA3 zone of hippocampus; whether the number of mossy fiber synapses on CA3 pyramidal neurons increases following ischemia; and whether the total number of granule cell neurons changes following global ischemia. It is also hypothesized that erythropoetin is induced in glial cells in the ischemic hippocampus, is released and acts on erythropoetin receptors on dentate progenitor cells to initiate proliferation of the progenitor cells and increased neurogenesis. Experiments will determine whether: erythropoetin and/or erythropoetin receptors are increased in hippocampus following global ischemia; whether ventricular infusion of erythropoetin increases neurogenesis from dentate progenitor cells; and whether ventricular infusion of antibodies to erythropoetin and/or erythropoetin receptors attenuate neurogenesis following global ischemia. These studies are important for understanding the mechanism of recovery of function following ischemic injury to the hippocampus.

描述（来自摘要）：新细胞在整个成人大脑中诞生 生活新生细胞的一个来源是齿状回的颗粒下区 海马体的一部分。新生细胞有形成神经元的潜力， 星形胶质细胞或少突胶质细胞。许多细胞出生在颗粒下区， 迁移到颗粒细胞层形成成熟的神经元。NMDA受体， 癫痫发作和应激激素调节这种神经发生。我们发现 缺血还上调神经发生。BrdU免疫组化法用于 在1-2周内，齿状颗粒下区的细胞出生增加了9倍 导致的脑缺血颗粒下区的新生细胞迁移 进入颗粒细胞层，其中60-66%成熟为神经元。一些细胞 出生于亚颗粒区的也迁移到齿状门，其中10-20% 变成星形胶质细胞。缺血诱导的齿状核神经发生不是由 内嗅皮层细胞死亡应激。本研究旨在 研究新生神经元的命运，并研究 啮齿动物脑中神经发生的缺血诱导。它是假设 全脑缺血后在齿状核中产生的神经元： 靶向CA 3锥体神经元;上调突触蛋白;增加 CA 3锥体神经元上的突触数量;并增加 齿状回颗粒细胞层的神经元。实验将决定：是否 逆行转运染料注射到海马CA 3区 与BrdU标记的细胞核和NeuN、MAP-2和calbindin神经元共定位 全脑缺血后齿状突颗粒细胞层中的标志物;是否 新生儿全脑缺血后突触前蛋白上调 海马CA 3区的神经元和苔藓纤维的数量 CA 3锥体神经元上的突触在缺血后增加; 全脑缺血后颗粒细胞神经元总数发生变化。是 我还假设，在缺血性脑损伤中， 海马，被释放并作用于齿状回上的红细胞生成素受体。 祖细胞以启动祖细胞的增殖，以及 增加神经发生。实验将确定是否： 海马体中的红细胞生成素受体和/或红细胞生成素受体增加， 缺血;脑室输注促红细胞生成素是否增加神经发生 以及心室输注抗体 对红细胞生成素和/或红细胞生成素受体的作用减弱神经发生 导致的脑缺血这些研究对于理解 海马缺血性损伤后功能恢复的机制。