Modeling Cellular Determinants of Cognitive Decline in Aging

衰老过程中认知能力下降的细胞决定因素建模

• 批准号: 8318136
• 负责人: PATRICK R HOF
• 金额: $ 40.82万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318136
• 关键词: Action Potentials; Address; Age; Aging; Animals; Architecture; Brain Diseases; Cell model; Cell physiology; Cells; Cereals; Communities; Computer software; Computing Methodologies; Custom; Data; Databases; Dendritic Spines; Dependence; Development; Disease; Electrophysiology (science); Financial compensation; Fluorescence Microscopy; Future; Genetic Programming; Goals; Image; Image Analysis; Impaired cognition; In Vitro; Ion Channel; Location; Macaca mulatta; Measurement; Measures; Membrane; Methods; Modeling; Monkeys; Morphology; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Pathologic; Pattern; Physiology; Prefrontal Cortex; Primates; Property; Pyramidal Cells; Resolution; Resources; Slice; Specific qualifier value; Structure; Synapses; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Vertebral column; age related; aged; base; behavior test; biocytin; cognitive function; design; human disease; innovation; insight; morphometry; multidisciplinary; new technology; normal aging; novel; parallel computing; patch clamp; postsynaptic; response; tool

PROJECT SUMMARY Cognitive decline in normal aging is accompanied by morphologic changes on many scales, and in rhesus monkeys, by single cell electrophysiological changes such as altered firing rates and synaptic responses. A subset of 'successful agers' can maintain both normal cognitive function and normal single-cell electrophysiology, suggesting some form of adaptive compensation for morphologic dystrophy at the cellular level. To date, no mechanistic understanding of these cellular changes, nor the inferred compensatory mechanisms, exists. The goal of this unique multidisciplinary project is to develop innovative computational technologies for identifying causal mechanisms underlying the cognitive decline that accompanies aging and neurodegeneration. Based upon these mechanisms, this project will design quantitatively precise strategies for compensating or reversing these changes, to restore a given cellular-level function to normal levels. Three Specific Aims will address this broad objective: (1) To reconstruct the morphology, including dendritic spines, of electrophysiologically characterized young and aged layer 3 (L3) pyramidal cells from the prefrontal cortex of rhesus monkeys that have underwent behavioral testing; (2) To develop morphologically accurate compartment models of young and aged L3 pyramidal cells while developing novel parameter optimization tools; and (3) To predict compensatory mechanisms for restoring normal function in aged or dystrophic neurons using newly-designed sensitivity-analysis techniques. Public dissemination of the 3D morphology and physiology of young and aged neurons from behaviorally characterized primates will provide a unique database for the general neuroscience community to begin to address important cellular and system-level questions. Dissemination of all modeling and analysis software will provide the computational community with efficient tools to apply and extend these techniques. Such studies will generate crucial insight into the cellular bases of aging- and neurodegenerative disease-related changes in cognitive function. The development of novel technologies to predict mechanisms that can compensate for specific morphologic changes to restore a given cellular level function, has far-reaching implications for designing therapeutic interventions for many human diseases.

项目概要 正常衰老过程中的认知能力下降伴随着许多方面的形态变化，在恒河猴中 猴子，通过单细胞电生理变化，例如放电率和突触反应的改变。一个 “成功老年人”的子集可以维持正常的认知功能和正常的单细胞 电生理学，表明细胞形态营养不良有某种形式的适应性补偿 等级。迄今为止，还没有对这些细胞变化的机制理解，也没有推断出的补偿 机制，存在。这个独特的多学科项目的目标是开发创新的计算 用于识别伴随衰老和认知能力下降的因果机制的技术 神经变性。基于这些机制，该项目将设计定量精确的策略 补偿或逆转这些变化，将特定的细胞水平功能恢复到正常水平。三 具体目标将解决这个广泛的目标：（1）重建形态，包括树突棘， 来自前额皮质的年轻和老年第 3 层 (L3) 锥体细胞的电生理学特征 经过行为测试的恒河猴； (2) 发展形态准确 年轻和老年 L3 锥体细胞的室模型，同时开发新的参数优化 工具; (3) 预测老年人或营养不良者恢复正常功能的代偿机制 使用新设计的敏感性分析技术的神经元。公开传播 3D 形态学和 来自行为特征灵长类动物的年轻和老年神经元的生理学将提供独特的 为一般神经科学界开始解决重要的细胞和系统级问题的数据库 问题。所有建模和分析软件的传播将为计算界提供 应用和扩展这些技术的有效工具。此类研究将对细胞产生重要的见解 衰老和神经退行性疾病相关认知功能变化的基础。的发展 预测可补偿特定形态变化的机制的新技术，以恢复 考虑到细胞水平的功能，对于为许多人设计治疗干预措施具有深远的影响 人类疾病。