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（海马依赖性情境恐惧条件反射，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和海马体在小鼠整个生命周期中的变化。在所有已测试较老生物体的物种中，包括人类，正常衰老对眨眼经典条件反射的影响类似。小鼠寿命短，基因组图谱丰富，并且具有执行许多认知和行为任务的能力，因此是了解与年龄相关的学习和记忆障碍的原因的宝贵资源。正常衰老过程中，各种大脑结构和相关认知能力受到不同程度的影响。在海马依赖性学习和记忆中，衰老与 CA1 锥体细胞功能能力下降有关，但神经元数量是稳定的。小脑依赖性学习和记忆与浦肯野细胞丢失以及与年龄相关的形态和功能损伤有关。传统上，学习、记忆和衰老的小脑和海马基质都是独立研究的。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，该机制负责与年龄相关的学习和记忆缺陷。目标 1 研究 C57BL/6 小鼠小脑皮层、深部核团和海马 CA1 区的神经元和胶质细胞数量以及几种形式的学习和记忆之间的关联。目标 2 探索年轻纯合子和老年杂合子浦肯野细胞变性 (pcd) 突变小鼠的神经元和胶质细胞数量以及学习能力。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：使用与人类衰老相似的方法对小鼠的寿命进行研究，有可能扩展关于作为学习和记忆基础的大脑区域的个体差异和差异性衰老的知识。美国和世界各地人们预期寿命的延长，增加了确定与年龄相关的认知缺陷的原因和治疗方法的紧迫性。该提案有可能扩大视野并设计治疗方法，以促进老年人的学习和记忆。