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; 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）：正常衰老的认知下降伴随着许多尺度上的形态变化，以及恒河猴中的形态学变化，单细胞电生理学变化，例如变化的点火率和突触反应。 “成功的老年人”的一个子集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的某种形式的适应性补偿。 迄今为止，尚无对这些细胞变化的机械理解，也没有推断出的补偿机制。 这个独特的多学科项目的目的是开发创新的计算技术，以识别衰老和神经变性伴随认知能力下降的因果机制。 基于这些机制，该项目将设计用于补偿或逆转这些变化的定量精确策略，以将给定的细胞级功能恢复到正常水平。 三个具体目的将解决这个广泛的目标：（1）重建来自电生理特征的年轻和年龄3（l3）锥体细胞的形态，包括恒河猴前额叶皮层，这些细胞经过了行为测试； （2）在开发新型参数优化工具的同时，开发了年轻和老年L3锥体细胞的形态准确的隔室模型； （3）使用新设计的灵敏度 - 分析技术预测恢复老年或营养不良神经元正常功能的补偿机制。 公众传播具有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，将为一般神经科学社区提供独特的数据库，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社区提供有效的工具，以应用和扩展这些技术。 这样的研究将产生对认知功能衰老和神经退行性相关的变化变化的细胞碱基的关键见解。 新型技术的发展，以预测可以补偿特定形态变化以恢复给定的细胞水平功能的机制，对许多人类疾病设计治疗干预措施具有深远的影响。 公共卫生相关性：该项目开发并验证了新的计算方法，以预测补偿性策略，以扭转正常衰老和神经退行性疾病伴随的病理变化的影响。 这些技术对设计脑部疾病的治疗干预具有深远的影响。 实现这些技术以及从认知表征动物的重建神经元形态和电生理数据的软件的公开分布是一般神经科学界的宝贵资源。