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.

项目摘要 正常衰老的认知能力下降伴随着许多尺度上的形态变化，在恒河猴中 猴子，通过单细胞电生理学的变化，例如发射速率和突触反应的改变。一个 “成功的老年人”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，提出了某种形式的适应性补偿，以对细胞处的形态营养不良 等级。迄今为止，尚无对这些细胞变化的机械理解，也没有推断的补偿性 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 识别衰老和衰老和认知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，以将给定的细胞级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）重建包括树突状刺的形态，， 来自电生理特征的年轻和老化层3（L3）锥体细胞来自前额叶皮层的 经过行为测试的恒河猴； （2）发展形态准确 在开发新的参数优化时，年轻和老年L3锥体细胞的隔室模型 工具; （3）预测恢复老年或营养不良的正常功能的补偿机制 使用新设计的灵敏度分析技术的神经元。公开传播3D形态和 具有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 一般神经科学界的数据库开始解决重要的蜂窝和系统级别 问题。所有建模和分析软件的传播将为计算社区提供 有效应用和扩展这些技术的工具。这样的研究将产生对细胞的关键见解 认知功能的衰老和神经退行性疾病相关的基础。发展的发展 预测可以补偿特定形态变化以恢复A的机制的新技术 给定细胞水平功能，对许多许多人设计治疗干预具有深远的影响 人类疾病。