Modeling Cellular Determinants of Cognitive Decline in Aging

项目总结 正常衰老的认知衰退伴随着许多尺度上的形态变化，在恒河猴中也是如此。 猴子，通过单细胞电生理变化，如放电频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，建议对细胞的形态营养不良进行某种形式的适应性补偿 水平。到目前为止，还没有对这些细胞变化的机械论理解，也没有推论的代偿 机制是存在的。这个独特的多学科项目的目标是开发创新的计算 用于识别伴随年龄和年龄增长的认知衰退的潜在因果机制的技术 神经退行性变。在这些机制的基础上，本项目将为 补偿或逆转这些变化，将给定的细胞水平功能恢复到正常水平。三 具体目标将针对这一广泛目标：(1)重建形态，包括树突刺， 电生理学特征的年轻和老年第三层(L3)锥体细胞来自前额叶皮质 经过行为测试的恒河猴；(2)发育形态准确 年轻和老年L3锥体细胞的隔室模型及其新的参数优化 工具；以及(3)预测老年人或营养不良患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形态和 来自行为特征的灵长类动物的年轻和老年神经元的生理学将提供独特的 用于普通神经科学界的数据库，开始处理重要的细胞和系统级别的问题 问题。所有建模和分析软件的传播将为计算界提供 应用和推广这些技术的有效工具。这样的研究将产生对细胞的关键洞察 与衰老和神经退行性疾病相关的认知功能改变的基础。的发展。 预测机制的新技术可以补偿特定的形态变化以恢复 鉴于细胞水平的功能，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。

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.