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: 8149833
• 负责人: PATRICK R HOF
• 金额: $ 35.96万
• 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/8149833
• 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; public health relevance; response; tool

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.

描述（由申请人提供）：正常衰老过程中的认知衰退伴随着多种尺度的形态变化，在恒河猴中，认知衰退伴随着单细胞电生理变化，例如放电率和突触反应的改变。 “成功的老年人”的一部分可以维持正常的认知功能和正常的单细胞电生理学，这表明在细胞水平上对形态营养不良存在某种形式的适应性补偿。 迄今为止，还不存在对这些细胞变化的机制理解，也不存在推断的补偿机制。 这个独特的多学科项目的目标是开发创新的计算技术，以识别伴随衰老和神经退行性病变的认知能力下降的因果机制。 基于这些机制，该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。 三个具体目标将实现这一广泛目标：(1) 重建经过行为测试的恒河猴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，包括树突棘； (2) 开发年轻和老年L3锥体细胞形态学上准确的室模型，同时开发新型参数优化工具； (3) 使用新设计的敏感性分析技术来预测恢复衰老或营养不良神经元正常功能的补偿机制。 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提供一个独特的数据库，以开始解决重要的细胞和系统级问题。 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。 此类研究将对衰老和神经退行性疾病相关认知功能变化的细胞基础产生重要的见解。 开发新技术来预测可以补偿特定形态变化以恢复给定细胞水平功能的机制，对于设计许多人类疾病的治疗干预措施具有深远的影响。 公共健康相关性：该项目开发并验证了新的计算方法，用于预测补偿策略，以扭转伴随正常衰老和神经退行性疾病的病理变化的影响。 此类技术对于设计脑部疾病的治疗干预措施具有深远的影响。 公开分发实现这些技术的软件以及来自认知特征动物的重建神经元形态和电生理学数据对于一般神经科学界来说是宝贵的资源。