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: 7029242
• 负责人: DIANA S WOODRUFF-PAK
• 金额: $ 39.43万
• 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/7029242
• 关键词: age difference; aging; association learning; behavioral /social science research tag; biological models; brain morphology; calcium channel; cell age; cerebellar Purkinje cell; cerebellum; conditioning; electrophysiology; excitatory aminoacid; gamma aminobutyrate; glutamate receptor; hippocampus; laboratory mouse; memory; mutant; neural plasticity; neural transmission; pyramidal cells; tissue /cell culture

DESCRIPTION (provided by applicant): 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. Aim 1 addresses 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.

描述（由申请人提供）：使用EykeBlink经典条件和其他形式的学习和记忆的模型系统（依赖海马依赖的上下文恐惧调节，小脑依赖的Rotorod），我们建议研究小脑和海马在鼠标中的结构和功能变化以及小脑和海马的结构和功能变化。正常衰老会影响所有已测试老年生物（包括人类）的所有物种中类似的拒绝经典条件。小鼠 - 寿命短，映射基因组以及执行许多认知和行为任务的能力 - 是一种宝贵的资源，可用于理解学习和记忆中与年龄相关的损害的原因。在正常衰老中，各种大脑结构和相关的认知能力受到差异影响。在海马依赖性学习和记忆中，衰老与CA1锥体细胞的功能能力降低有关，但神经元数稳定。小脑依赖性学习和记忆与形态和功能中与年龄相关的浦肯野细胞丧失以及与年龄相关的障碍有关。传统上，已经独立研究了学习，记忆和衰老的小脑和海马底物。该提案的主要目的是使用小鼠模型来测试有关小脑依赖性和海马依赖性机制的假设，这些机制负责学习和记忆中与年龄相关的缺陷。 AIM 1解决了小脑皮层与深核和海马CA1场中神经元和神经胶质数之间的关联，以及C57BL/6小鼠中的几种学习和记忆形式。 AIM 2探索了年轻的纯合子和衰老的杂合普肯野细胞变性（PCD）突变小鼠的神经元和神经胶质数和学习。目标3和4分别检查海马和小脑切片中神经元的功能衰老。 AIM 5启动了GABA输注潜力减轻学习受损的潜力的试点测试。相关性：使用与人类衰老相似的措施对小鼠的寿命进行研究，有可能扩展有关学习和记忆的基材的大脑区域中个体变异和差异衰老的知识。美国和世界人民的预期寿命延长，增加了需要确定与年龄相关的认知缺陷的原因和治疗方法的紧迫性。该提议有可能扩大观点并设计治疗方法，以促进老年人的学习和记忆。