Modeling Cellular Determinants of Cognitive Decline in Aging

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学变化， 猴子，通过单细胞电生理变化，如改变放电率和突触反应。一 一部分“成功老年人”既能保持正常认知功能， 电生理学，这表明在细胞的形态学营养不良的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制性理解，也没有推断出补偿性变化。 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 用于识别伴随衰老的认知能力下降的因果机制的技术， 神经变性根据这些机制，本项目将设计定量精确的战略， 补偿或逆转这些变化，以将给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， 的电生理特征的年轻和老年第3层（L3）锥体细胞从前额叶皮层的， 恒河猴进行了行为测试;（2）发展形态准确 年轻和老年L3锥体细胞的房室模型，同时开发新的参数优化 工具;（3）预测老年或营养不良患者恢复正常功能的代偿机制 神经元使用新设计的灵敏度分析技术。公开传播3D形态学， 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一个独特的 数据库的一般神经科学界开始，以解决重要的细胞和系统水平 问题.所有建模和分析软件的传播将为计算界提供 有效的工具来应用和扩展这些技术。这些研究将产生关键的洞察细胞 衰老和神经退行性疾病相关的认知功能变化的基础。的发展 新的技术来预测机制，可以补偿特定的形态学变化，以恢复一个 考虑到细胞水平的功能，对于设计许多人的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.