Mechanisms of Associative Learning in Aging: Mouse Models

衰老中的联想学习机制：小鼠模型

• 批准号: 7569304
• 负责人: DIANA S WOODRUFF-PAK
• 金额: $ 37.57万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569304
• 关键词: AMPA Receptors; Activities of Daily Living; Address; Affect; Age; Age-associated memory impairment; Aging; Astrocytes; Axon; Behavior; Behavioral; Biological Models; Blinking; Brain; Brain region; C57BL/6 Mouse; Calcium Channel; Cell Count; Cell Nucleus; Cerebellar cortex structure; Cerebellum; Cognitive; Cognitive aging; Dendrites; Elderly; Electrophysiology (science); Fiber; Genome Mappings; Hippocampus (Brain); Human; Impairment; Individual; Infusion procedures; Knowledge; Learning; Life; Life Expectancy; Long-Term Depression; Long-Term Potentiation; Longevity; Measures; Memory; Modeling; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Mutation; N-Methylaspartate; Neuroglia; Neurologic; Neurons; Organism; Oryctolagus cuniculus; Outcome; Performance; Preparation; Procedures; Process; Purkinje Cells; Pyramidal Cells; Research; Research Personnel; Resources; Role; Slice; Structure; Synaptic Transmission; System; Testing; United States; Variant; age effect; age related; base; behavior test; classical conditioning; cognitive function; conditioned fear; conditioning; early onset; gamma-Aminobutyric Acid; granule cell; hippocampal pyramidal neuron; inhibitory neuron; motor learning; mouse model; mutant; neuron loss; normal aging; programs; voltage

Using the model system of eyeblink classical conditioning and other forms of learning and memory (hippocampus-dependent contextual fear conditioning, cerebellum-dependent rotorod), we propose to investigate structural and functional changes and associated mechanisms in the cerebellum and hippocampus over the life span in the mouse. Normal aging affects eyeblink classical conditioning similarly in all species in which older organisms have been tested, including humans. Mice - with their short life span, mapped genome, and capacity to perform a number of cognitive and behavioral tasks - are an invaluable resource to use for understanding causes of age-related impairment in learning and memory. Various brain structures and associated cognitive capacities are differentially affected in normal aging. In hippocampus- dependent learning and memory, aging is associated with reduced functional capacity of CA1 pyramidal cells, but neuron number is stable. Cerebellum-dependent learning and memory is associated with Purkinje cell loss and age-related impairment in morphology as well as function. Traditionally, cerebellar and hippocampal substrates of learning, memory, and aging have been studied independently. The major aim of this proposal is to use mouse models to test hypotheses about cerebellar-dependent and hippocampus- dependent mechanisms responsible for age-related deficits in learning and memory. Aims 1 address associations between neuron and glia numbers in cerebellar cortex and deep nuclei and hippocampal CA1 fields and several forms of learning and memory in C57BL/6 mice. Aim 2 explores neuron and glia number and learning in young homozygous and aging heterozygous Purkinje cell degeneration (pcd) mutant mice. Aims 3 and 4 examine functional aging of neurons in hippocampal and cerebellar slices, respectively. Aim 5 initiates pilot testing of the potential of GABA infusions to ameliorate impaired learning. Relevance: Research over the life span of mice using measures with parallels to human aging has the potential to extend knowledge about individual variation and differential aging in brain regions that are the substrates of learning and memory. The extended life expectancy of people in the United States and the world adds urgency to the need to identify causes and treatments for age-related cognitive deficits. This proposal has the potential to expand perspectives and devise treatments to facilitate learning and memory in older adults.

使用眨眼经典条件反射和其他形式的学习和记忆的模型系统 （海马体依赖性情境恐惧调节，小脑依赖性旋转杆），我们建议 研究小脑的结构和功能变化以及相关机制 小鼠一生中的海马体。正常衰老对眨眼经典条件反射的影响类似 所有对较古老的生物体进行过测试的物种，包括人类。老鼠——寿命短， 绘制基因组图谱，以及执行许多认知和行为任务的能力 - 是无价的 用于了解与年龄相关的学习和记忆障碍的原因的资源。各种脑 结构和相关认知能力在正常衰老过程中受到不同程度的影响。在海马体中—— 依赖学习和记忆，衰老与 CA1 锥体功能能力下降有关 细胞，但神经元数量是稳定的。小脑依赖性学习和记忆与浦肯野病有关 细胞损失以及与年龄相关的形态和功能损伤。传统上，小脑和 学习、记忆和衰老的海马基质已被独立研究。主要目标是 该提议是使用小鼠模型来测试有关小脑依赖性和海马体的假设 导致与年龄相关的学习和记忆缺陷的依赖机制。目标 1 地址 小脑皮层、深部核团和海马 CA1 中神经元和胶质细胞数量之间的关联 C57BL/6 小鼠的领域和几种形式的学习和记忆。目标 2 探索神经元和神经胶质细胞数量 以及年轻纯合子和老年杂合子浦肯野细胞变性（pcd）突变小鼠的学习。 目标 3 和 4 分别检查海马和小脑切片中神经元的功能老化。目标 5 启动了 GABA 输注改善学习障碍潜力的试点测试。相关性：研究 使用与人类衰老相似的措施来延长小鼠的寿命有可能延长 关于作为学习基础的大脑区域的个体差异和差异老化的知识 和记忆。美国和世界各地人民预期寿命的延长增加了解决这一问题的紧迫性 需要确定与年龄相关的认知缺陷的原因和治疗方法。该提案有潜力 扩大视野并设计治疗方法以促进老年人的学习和记忆。