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Mechanisms of Age-related Cognitive Decline in the Rhesus Monkey

恒河猴与年龄相关的认知衰退的机制

基本信息

批准号：
10360467
负责人：
PATRICK R HOF
金额：
$ 55.39万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360467
关键词：
3-Dimensional Action Potentials Adult Age-associated memory impairment Aging Anatomy Anti-Inflammatory Agents Antioxidants Axon Back Behavior Behavior assessment Behavioral Biological Markers Blood Vessels Blood capillaries Brain Cell physiology Cells Characteristics Cognitive Communities Computer Models Curcumin Data Dendritic Spines Electron Microscopy Elements Excitatory Synapse Exhibits Frequencies Functional disorder Funding Glutamates Goals Immunofluorescence Immunologic Immunohistochemistry Impaired cognition In Situ In Vitro Individual Inflammation Inflammatory Inhibitory Synapse Interneurons Intervention Laser Scanning Confocal Microscopy Lateral Location Longevity Macaca mulatta Membrane Methods Microglia Mitochondria Modeling Molecular Molecular Profiling Monkeys Morphology Myelin Myelin Sheath Neuroglia Neuronal Dysfunction Neurons Neuropil Neurosciences Neurotransmitter Receptor Organelles Oxidative Stress Pathway interactions Pattern Physiological Population Predisposition Prefrontal Cortex Primates Property Proteins Pyramidal Cells Research Resources Short-Term Memory Slice Stimulus Synapses Testing Therapeutic Therapeutic Intervention United States National Institutes of Health V1 neuron Vascular Diseases Visual Visual Cortex age effect age group age related aged aging population animal tissue area striata biocytin brain dysfunction brain tissue cognitive function cohort comparative computer framework cytokine density design dietary excitatory neuron hippocampal pyramidal neuron improved functioning inhibitory neuron insight middle age molecular phenotype molecular scale multidisciplinary network models normal aging novel oculomotor patch clamp polyphenol postsynaptic prevent protein biomarkers relating to nervous system targeted treatment ultra high resolution

项目摘要

During normal aging in the rhesus monkey, pyramidal cells in the dorsolateral prefrontal cortex (LPFC) undergo significant structural and functional changes that are likely associated with cognitive impairment, while pyramidal cells in the primary visual cortex (V1) are comparatively spared. The overall hypothesis of this project is that selective vulnerability of neurons and associated networks in LPFC compared to V1 during aging is due to a greater susceptibility to increases in oxidative stress, inflammation, and vascular dysfunction in LPFC than in V1. We further hypothesize that intervention with the potent antioxidant and anti-inflammatory polyphenol curcumin will prevent or reduce age-related dysfunction on multiple scales- from the molecular to the behavioral level. This project has three aims: 1) To assess the biomarker and ultrastructural characteristics of V1 and dlPFC neuropil. In situ immunofluorescence multiplexing of ~30 protein biomarkers will be used to determine the molecular phenotype of neurons, glia, vasculature and surrounding neuropil with a GE Global Research platform tailored for use in brain tissue, enabling quantitative, multimarker analyses with high throughput. Using 2D and 3D electron microscopy, inhibitory and excitatory synapses, mitochondria, myelin and axons of neurons as well as microglia and vascular elements will be quantitatively characterized. 2) To characterize the physiological and morphological properties of layer 3 (L3) pyramidal neurons and of interneurons in V1 and dlPFC across the adult lifespan of rhesus monkeys. Using whole-cell patch-clamp recordings we will assess passive membrane properties, AP firing patterns and underlying ionic currents, as well as excitatory and inhibitory postsynaptic currents of L3 excitatory and inhibitory neurons in in vitro slices of PFC and V1. We will then characterize the morphological properties (e.g. dendritic topology, density and detailed morphology of dendritic spines and neurotransmitter receptor and transporter distribution, as well as oxidative stress markers) of these same neurons using immunohistochemistry and ultra-high resolution confocal laser scanning microscopy. 3) To use computational models of V1 and dlPFC networks to predict the functional consequences—at the single neuron, network and behavioral levels—of changes revealed in Aims 1 and 2. Simplified models of LPFC and V1 neurons will be incorporated into model networks capable of persistent neural activity, oculomotor spatial working memory, and visual orientation tuning. Unique to this proposal is the combination of state-of-the art anatomical, physiological, and computational approaches together with concurrent behavioral assessment of the aging monkey under control conditions and following therapeutic treatment with curcumin. This project will yield entirely novel and critically needed information on the neural substrates of cognitive decline in the aging primate and provide important insight into the specific mechanisms of action of protective anti-inflammatory and anti-oxidants during normal aging.

在恒河猴正常衰老过程中，背外侧前额叶皮层（LPFC）的锥体细胞