AGING VULNERABILITY TO EXCITATORY AMINO ACIDS

这项研究计划旨在了解 认知和行为能力下降的神经化学和行为相关性 记忆与年龄和阿尔茨海默病(AD)的关系。最终目标是 开发预防或改善这种下降的治疗方法。 研究的重点是大鼠核内与年龄相关的变化。 基底大细胞(NBM)，类似于基底核的区域 人类体内的Meynert。在正常衰老和AD期间，大脑发育为 退行性改变的复杂模式，包括但不限于， 作为正常机制基础的特定神经系统的丧失 与记忆相关联。延髓基底核细胞的丢失 Meynert可能对这种记忆障碍负责。这个世界的本质 导致NBM内细胞退化的选择过程 是未知的，尽管内源性兴奋性氨基酸已经 牵连其中。此外，此中的一个或多个单元的标识 其退化导致记忆发育的核 损伤，也是未知的。人们的假设是，失去 胆碱能细胞足以产生记忆缺陷。上一首 这个实验室的研究引起了人们对 这一假设的正确性。然而，NBM区域包含许多 非胆碱能神经递质系统及其在增龄和衰老中的作用 痴呆症相关的记忆缺陷还没有被研究过。 这个项目解决了以下与机制相关的假说 NBM神经元细胞死亡与衰老的关系：如果NBM中的神经元 表现出与年龄相关的兴奋性氨基酸的差异性易感性 酸性神经毒素，如2-氨基-3-羟基-5-甲基异恶唑-4- 本草酸(AMPA)或N-甲基-D-天冬氨酸(NMDA)，然后这些 神经毒素应产生不同的行为和生化反应 对幼鼠、成年鼠和老年鼠的影响。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 发展中的行为变化；检查组织学和 损伤后大脑的生化变化；以及相互关系 特异神经元标志物的变化与运动能力的关系 行为任务。这些实验对我们的 对特定NBM神经元差异易损性的理解 随着年龄的增长。

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.