AGING VULNERABILITY TO EXCITATORY AMINO ACIDS

衰老对兴奋性氨基酸的脆弱性

• 批准号: 2051781
• 负责人: Gary L. Wenk
• 金额: $ 13.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-08 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2051781
• 关键词: Alzheimer's disease; age difference; aging; behavior test; biological models; cell death; excitatory aminoacid; experimental brain lesion; laboratory rat; memory disorders; neuropharmacology; neurotoxins; substantia innominata

This research program is directed towards an understanding of the neurochemical and behavioral correlates of the decline in cognition and memory with age and in Alzheimer's Disease (AD). The ultimate goal is the development of preventative or ameliorative treatments for this decline. The investigations focus on age-associated changes in the rat nucleus basalis magnocellularis (NBM), an area analogous to the nucleus basalis of Meynert in humans. During normal aging and in AD the brain develops a complicated pattern of degenerative changes including, but not limited to, the loss of specific neural systems that underlie the normal mechanisms associated with memory. The loss of cells in the nucleus basalis of Meynert may be responsible for this memory impairment. The nature of the selection process that leads to the degeneration of cells within the NBM is unknown, although endogenous excitatory amino acids have been implicated. In addition, the identity of the cell, or cells, in this nucleus whose degeneration leads to the development of the memory impairment, is also unknown. The assumption has been that the loss of cholinergic cells is sufficient to produce the memory deficit. Previous research from this laboratory has raised significant doubt about the validity of this assumption. However, the NBM region contains many noncholinergic neurotransmitter systems and their role in age- and dementia-associated memory deficits has not been investigated. This project addresses the following hypothesis related to the mechanisms of NBM neuronal cell death associated with aging: if neurons in the NBM demonstrate an age-related differential vulnerability to excitatory amino acid neurotoxins, such as 2-amino-3-hydroxy-5-methylisoxazole-4- proprionicacid (AMPA) or N-methyl-d-aspartate (NMDA), then these neurotoxins should produce differential behavioral and biochemical consequences in young, adult and old rats. This hypothesis will be tested by producing lesions within the basal forebrain of rats; studying the behavioral changes that develop; examining the histological and biochemical changes in the brain following the lesions; and correlating the changes in specific neuronal markers with performance in the behavioral tasks. These experiments have significant implications for our understanding of the differential vulnerability of specific NBM neurons with aging.

这项研究计划旨在了解 认知能力下降的神经化学和行为相关性， 记忆力随年龄增长和阿尔茨海默病（AD）。最终目标是 开发针对这种下降的预防性或改善性治疗。 研究的重点是大鼠核团中与年龄相关的变化 基底大细胞（NBM），一个类似于基底核的区域 人类的Meynert在正常衰老和AD中，大脑会产生一种 退行性变化的复杂模式，包括但不限于， 作为正常机制基础的特定神经系统的丧失 与记忆有关。基底核细胞的丢失 Meynert可能对这种记忆障碍负责。 的性质 导致NBM内细胞变性的选择过程 是未知的，虽然内源性兴奋性氨基酸已被 牵连此外，该细胞中的一个或多个细胞的身份也可以被确定。 退化导致记忆发展的核 损伤，也是未知的。 假设是， 胆碱能细胞足以产生记忆缺陷。先前 该实验室的研究对 这个假设的有效性。 然而，NBM区域包含许多 非胆碱能神经递质系统及其在年龄和 痴呆症相关的记忆缺陷尚未被研究。 本项目涉及以下与机制相关的假设 NBM神经元细胞死亡与衰老相关：如果NBM中的神经元 表现出与年龄相关的对兴奋性氨基酸的脆弱性差异 酸性神经毒素，如2-氨基-3-羟基-5-甲基异恶唑-4-基， 丙酸（AMPA）或N-甲基-d-天冬氨酸（NMDA），则这些 神经毒素会产生不同的行为和生化反应， 对年轻、成年和老年大鼠的影响。这一假设将得到检验 通过在大鼠的基底前脑内产生损伤;研究 发展的行为变化;检查组织学和 病变后脑中的生化变化;以及 特异性神经元标记物的变化与 行为任务这些实验对我们的研究具有重要意义。 了解特定NBM神经元的差异脆弱性 随着年龄的增长。