DOPAMINERGIC AND BASAL PLASTICITY IN AGING

衰老过程中的多巴胺能和基础可塑性

• 批准号: 3091285
• 负责人: FRANZ F HEFTI
• 金额: $ 70.87万
• 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: 1991-06-01 至 1996-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3091285
• 关键词: aging; basal ganglia; dopamine; neural plasticity

Understanding underlying alteration in brain function is a prerequisite for the amelioration of age-related behavioral impairments and age-related neurodegenerative diseases which represent major problems for advanced societies. Research during the past decade has revealed that age-related morphological and physiological changes in neuron function can not be generalized to all neurons in the central nervous system but are brain region and cell type specific. In addition, recent studies have suggested that some neural functions successfully maintained with age may depend on the ability of neurons to preserve or repair their neural circuitry in response to naturally occurring cell loss, deafferentation or neurotransmitter deficits. Understanding these cellular mechanisms will provide a basis for the development of future therapeutic strategies aimed a amelioration of age-related neurodegenerative diseases. The proposed program project aims at contributing to such progress by providing information on age-related changes in basal ganglia function of the mammalian brain. Basal ganglia play a central role in motor function and are also involved in functions related to cognitive and emotional behavior. Disturbances in these behaviors are a clinical feature in some, but no all, elderly individuals and neuropathological changes in the basal ganglia are the hallmark of several neurodegenerative diseases, including Huntington's and Parkinson's disease. Emphasis is given to dopaminergic neurons whose degeneration is responsible for the majority of parkinsonian symptoms. The study of plasticity, neuronal death and age-related functional changes represent the main area of focus of the program project. Plasticity is a normal feature of a developing nervous system. While less frequent in the adult and aging nervous system, plasticity can occur in response to age- or disease-induced degenerative processes. The program project aims at establishing the extent of changes in plasticity of basal ganglia neurons induced by aging and injury. Neuronal atrophy an degeneration of selected neuronal populations accompanies aging and selective neuronal death is a key feature of neurodegenerative diseases. Several specific aims of the program project are directed at understanding molecular mechanisms playing a key role in determining the consequences of aging or of experimental injury to the brain. Attempts to prevent neuronal degeneration by the pharmacological use of protein growth factors or compounds altering transmitter functions is a central theme in the program project. Functional adaptations to aging have been partly characterized for dopaminergic but not other basal ganglia neurons. A specific aim of this program project is to study the molecular basis of selected age-related functional changes in the dopaminergic system. An entire project aims at providing the first thorough description of age-related changes in electrophysiological behavior of basal ganglia neurons. Preliminary findings reported in this application suggest that aging does not generally produce neuronal atrophy or impair plasticity and functional adaptation of basal ganglia neurons. The possibility that basal ganglia undergo unique age-related changes retaining the ability for plasticity and functional adaptation represents a key hypothesis to be tested. The proposed experiments will help to understand the molecular basis of plasticity and adaptation.

了解大脑功能的潜在变化是 年龄相关性行为障碍的改善和年龄相关性 神经退行性疾病是晚期患者面临的主要问题 社会。过去十年的研究表明，与年龄相关的 神经功能的形态和生理变化不能 泛指中枢神经系统中的所有神经元，但大脑 区域和单元格类型特定。此外，最近的研究表明， 一些随着年龄增长而成功维持的神经功能可能依赖于 神经元保护或修复其神经回路的能力 对自然发生的细胞丢失、去传入或 神经递质缺乏。了解这些细胞机制将 为未来治疗策略的发展提供基础 与年龄相关的神经退行性疾病的改善。建议数 方案项目旨在通过提供 老年人基底节功能的增龄性变化信息 哺乳动物的大脑。基底节在运动功能和 也参与了与认知和情绪行为相关的功能。 这些行为障碍是一些患者的临床特征，但不是全部， 老年人与基底节的神经病理改变 包括亨廷顿氏症在内的几种神经退行性疾病的特征 和帕金森氏症。重点是多巴胺能神经元，其 变性是帕金森氏症的主要症状。 可塑性、神经元死亡和增龄相关功能改变的研究 代表计划项目的主要重点领域。可塑性是一种 神经系统发育的正常特征。虽然不太频繁地在 成年和老化的神经系统，可塑性可以发生在年龄的反应-或 疾病引起的退化过程。该方案项目旨在 建立基底神经节神经元可塑性变化的程度 由衰老和损伤引起的。神经细胞萎缩和退行性变 神经元种群伴随着衰老，选择性神经元死亡是一种 神经退行性疾病的主要特征。该计划的几个具体目标 计划项目旨在了解分子机制在其中的作用 在决定老化或实验的后果方面发挥关键作用 脑部受伤。试图通过以下方式防止神经元退化 蛋白质生长因子或化合物的药理学应用 发射机功能是该方案项目的中心主题。 对衰老的功能适应在一定程度上表现为 多巴胺能神经元，而不是其他基底节神经元。这样做的一个具体目的是 计划项目是研究选定的与年龄相关的分子基础 多巴胺能系统的功能变化。整个项目旨在 首次对与年龄相关的变化进行了全面描述 基底神经节神经元的电生理行为。 在这项申请中报告的初步发现表明，衰老 一般不会导致神经元萎缩或损害可塑性和功能 基底神经节神经元的适应性。基底节有可能 经历独特的与年龄相关的变化，保持可塑性和 功能适应是一个有待检验的关键假说。这个 拟议中的实验将有助于理解 可塑性和适应性。