Modeling Cellular Determinants of Cognitive Decline in Aging

描述（由申请人提供）：正常衰老的认知能力下降伴随着许多尺度的形态学变化，在恒河猴中，通过单细胞电生理变化，如放电速率和突触反应的改变。一部分“成功的老年人”可以维持正常的认知功能和正常的单细胞电生理，这表明在细胞水平上对形态营养不良有某种形式的适应性补偿。到目前为止，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。这个独特的多学科项目的目标是开发创新的计算技术，以确定伴随衰老和神经变性的认知能力下降的因果机制。基于这些机制，本项目将设计定量精确的策略来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。三个具体目标将解决这一广泛的目标：(1)重建年轻和年老的三层（L3）锥体细胞的电生理学特征，包括树突棘，从接受行为测试的恒河猴前额皮质；(2)在开发新的参数优化工具的同时，建立年轻和老年L3锥体细胞形态学准确的室室模型；(3)利用新设计的灵敏度分析技术预测衰老或营养不良神经元恢复正常功能的代偿机制。公开传播来自行为特征灵长类动物的年轻和老年神经元的3D形态和生理学，将为一般神经科学界开始解决重要的细胞和系统级问题提供一个独特的数据库。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。这些研究将对衰老和神经退行性疾病相关的认知功能变化的细胞基础产生至关重要的见解。新技术的发展预测了能够补偿特定形态变化以恢复给定细胞水平功能的机制，对设计针对许多人类疾病的治疗干预具有深远的意义。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project develops and validates novel computational methods for predicting compensatory strategies to reverse the effects of pathologic changes accompanying normal aging and neurodegenerative disorders. Such technologies have far-reaching implications for designing therapeutic interventions in brain diseases. Public distribution of the software that implements these technologies and of the reconstructed neuron morphologies and electrophysiological data from cognitively characterized animals is an invaluable resource to the general neuroscience community.