MODULATION OF NEURONAL PLASTICITY IN THE HIPPOCAMPUS

海马体神经元可塑性的调节

• 批准号: 2839346
• 负责人: THOMAS Hugh MCNEILL
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-30 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2839346
• 关键词: acetylcholine; age difference; animal old age; brain injury; denervation; dentate gyrus; electrophysiology; experimental brain lesion; hippocampus; histopathology; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; nervous system regeneration; neural growth associated protein; neural plasticity; neuroanatomy; neurogenesis; neurotrophic factors; synaptogenesis; western blottings

DESCRIPTION (from applicant's abstract) This project seeks to identify the cellular mechanisms that regulate neurite outgrowth and synapse replacement in the hippocampus in response to injury and the effect of aging on these processes. Studies conducted during the previous funding period argue against the notion that reactive synaptogenesis involves a unitary set of cellular responses common to all neurons in the brain but more likely involves specific sets of partially overlapping developmental signals that are cell type, brain region and lesion specific. In addition, while it was once believed that degenerative disease of the brain can be represented by simple cell loss that leads to functional decline, it is now known that the injured brain represents a composite of various adaptive responses which work to preserve and repair the brain's synaptic circuits against a background of ongoing cell death. However, while previous anatomical studies have readily demonstrated the ability of neurons to adapt and form new synaptic circuits in response to brain injury the cellular and molecular mechanisms that regulate reactive synaptogenesis and the effect of aging on these processes remain unclear. The studies proposed are a direct extension of the work completed previously and will test three working hypotheses: 1) that the observed delayed but enhanced sprouting response of commissural/associational axons following a combined lesion of the entorhinal cortex/fimbria fornix (EC/FF) is selective for the loss of cholinergic input from the septum/diagonal band and input from the entorhinal cortex; 2) that in response to injury different sets of growth associated proteins and trophic factors regulate neurite outgrowth in projection neurons that terminate in different laminae of the dentate gyrus (DG); and 3) that the new pattern of synaptic innervation that is formed in the DG following the EC/FF lesion results in the formation of a pattern of aberrant neural circuits which increases the vulnerability of target neurons to injury, inhibits information processing and thus, limits the chance of functional recovery. The investigators will use experimental deafferentation lesions in rats to model different combinations of neurotransmitter deficits that may affect neurite outgrowth and synapse replacement in the DG following brain injury. In addition, they will screen aged rats prior to surgery, using the Morris water maze, to identify subsets of old rats with hippocampal deficits that may alter their ability to respond to the lesion. They will also assess the rate of functional recovery at various times postlesion to correlate with their morphological and molecular data. Morphological remodeling of afferent input to the DG will be evaluated using light microscopic histochemical and ultrastructural methods; while the synaptic physiology of the anatomically reorganized hippocampus will be examined by electrophysiological analysis. In addition, they will use in situ hybridization and western blot methods to define the time course of changes in the levels of mRNAs and proteins that they hypothesize are associated with the promotion of neurite outgrowth and synapse replacement in the hippocampus (i.e. GAP-43, SCG-10, BDNF, trkB and SNAP-25).

描述（来自申请人的摘要） 该项目旨在确定调节的细胞机制 在海马中的神经突产物和突触替代响应 受伤和衰老对这些过程的影响。进行的研究 在上一个资金期间，反对反应性的概念 突触发生涉及一组统一的细胞反应 大脑中的所有神经元，但更有可能涉及特定集合 细胞类型的部分重叠的发育信号，大脑 特定于区域和病变。另外，曾经相信 大脑的退行性疾病可以通过简单的细胞损失来表示 这导致功能下降，现在知道受伤的大脑 代表各种适应性反应的综合 在背景下保存和修复大脑的突触电路 持续的细胞死亡。但是，尽管以前的解剖学研究 很容易证明神经元适应和形成新的能力 突触电路响应脑损伤，细胞和分子 调节反应性突触发生的机制和衰老的作用 在这些过程中仍不清楚。 提出的研究是完成工作的直接扩展 以前并将检验三个工作假设：1）观察到的 延迟但增强的连续性/关联的发芽响应 轴突结合病变的轴突/纤维膜的组合病变 Fornix（EC/FF）对丧失胆碱能输入的选择有选择性 隔膜/对角线带和来自内嗅皮层的输入； 2） 对伤害的反应不同的生长蛋白相关蛋白和 营养因子调节投射神经元中神经突的生长 终止于齿状回（DG）的不同层层； 3） DG中形成的新突触神经支配模式 遵循EC/FF病变导致形成 异常的神经回路，增加了目标的脆弱性 神经元受伤，抑制信息处理，因此限制了 功能恢复的机会。 研究人员将使用大鼠的实验性脱落病变 建模可能的神经递质缺陷的不同组合 影响神经突产物的生长和突触替代DG以下 脑损伤。此外，他们将在手术前筛查老化的大鼠， 使用莫里斯水迷宫，以确定与 海马缺陷可能会改变他们对响应的能力 病变。他们还将评估各种功能回收率 与它们的形态和分子相关的时代。 数据。 DG传入输入的形态学重塑将是 使用光学微观组织化学和超微结构进行评估 方法;而解剖学重新组织的突触生理 海马将通过电生理分析检查。在 此外，他们将使用原位杂交和蛋白质印迹方法 定义mRNA和蛋白质水平变化的时间过程 他们假设与促进神经突有关 海马中的产物和突触替代（即GAP-43， SCG-10，BDNF，TRKB和SNAP-25）。