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Synaptic plasticity across the lifespan

整个生命周期的突触可塑性

基本信息

批准号：
10643839
负责人：
KRISTEN M HARRIS
金额：
$ 56.55万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643839
关键词：
3-Dimensional ARHGEF5 gene Acceleration Actin-Binding Protein Adult Age Animals Axon Behavioral Biological Brain Brain Diseases Calcium Caliber Cell model Dendrites Dendritic Spines Development Developmental Therapeutics Program Distant Electron Microscopy Equilibrium Excitatory Synapse Foundations Future Genes Goals Growth Hippocampus Hour Image Impaired cognition Impairment Information Storage Inhibitory Synapse Integral Membrane Protein Knock-out Knowledge Label Learning Light Lipids Long-Term Potentiation Longevity Measures Mediating Memory Modeling Molecular Mus Organelles Outcome Pattern Polyribosomes Positioning Attribute Post-Translational Protein Processing Process Protein Biosynthesis Proteins Rattus Regulation Research Resources ST5 gene Site Smooth Endoplasmic Reticulum Specificity Structure Synapses Synaptic plasticity Testing Vertebral column Weaning age related aged aging brain aging hippocampus behavior measurement cognitive capacity dentate gyrus entorhinal cortex granule cell insight lipid transport nanometer resolution novel strategies novel therapeutics optogenetics p38 Mitogen Activated Protein Kinase postnatal postsynaptic presynaptic reconstruction response senescence synaptogenesis synaptopodin young adult

项目摘要

The overall goal is to understand synaptic mechanisms of learning and memory. Long-term potentiation (LTP) is a model of learning and memory that is well-suited to investigate these processes. Dendritic spines host about ninety percent of excitatory synapses in the brain and are well known to show structural plasticity following induction of LTP. The developmental onset of dendritic spines coincides with an abrupt developmental onset for LTP lasting more than three hours (L-LTP) at postnatal day 12 (P12) in rat hippocampus. At P10 and P15, LTP enhances synaptogenesis and small spine formation. With maturation, the LTP-accelerated synaptogenesis shifts to a process that enlarges specific synapses and retains spine clusters locally but is balanced by reduction in spine numbers elsewhere on the dendrite. The spine clusters are locally delimited by the availability of smooth endoplasmic reticulum (SER), an organelle critical for regulating calcium, and the transport of lipids and proteins, and by the presence of polyribosomes, which mediate local protein synthesis. The LTP-produced synapse enlargement is greatest on spines that contain a spine apparatus, which is a structure derived from SER that provides synthesis and post-translational modification of transmembrane proteins. Structural changes in presynaptic axons are also developmentally regulated following LTP and mirror the spine changes with new boutons forming to accommodate the LTP-accelerated synaptogenesis at P15, and fewer boutons occurring with spine reduction at P60. Thus, LTP in developing hippocampus accelerates synaptogenesis, whereas resource-dependent synapse growth and spine clustering occur on mature dendrites. This homeostatic balance in synaptic plasticity is hypothesized to be disrupted with cognitive decline in the aging brain. A comprehensive analysis of structural synaptic plasticity during maturation and senescence is proposed as a foundation for understanding lifelong changes in cognitive capacity. Specifically, the aims are: Aim 1: Evaluate the maturation of resource-dependent synaptic growth and clustering. Aim 2: Determine circuit generality and synapse specificity of resource-dependent growth and clustering. Aim 3: Determine synaptic foundation of cognitive capacity and decline in the aging hippocampus. Aim 4: Test importance of the spine apparatus in synapse growth and clustering. Outcomes promise essential insight into the synaptic basis of learning and memory across lifespan and will provide basic knowledge that could inform new therapies for developmental and age-related brain disorders.

总体目标是了解学习和记忆的突触机制。长时程增强是一个学习和记忆的模型，非常适合研究这些过程。树突棘的宿主大约大脑中90%的兴奋性突触，并且众所周知，诱导LTP。树突棘的发育开始与一个突然的发育开始相一致，生后第12天（P12）大鼠海马LTP持续时间超过3小时（L-LTP）。在P10和P15，LTP 增强突触发生和小棘形成。随着成熟，LTP加速突触发生，转移到扩大特定突触并局部保留棘簇但通过减少来平衡的过程树突上其他地方的棘数。脊柱集群由平滑的可用性局部界定。内质网（SER），一种对调节钙以及脂质和蛋白质运输至关重要的细胞器，以及介导局部蛋白质合成的多核糖体的存在。LTP产生的突触在含有棘器的棘上，增大最大，棘器是源自SER的结构，提供跨膜蛋白的合成和翻译后修饰。结构性变化突触前轴突在LTP后也受到发育调节，并反映了新的LTP引起的脊柱变化。终扣形成，以适应LTP加速的突触发生在P15，和较少的终扣发生， P60脊柱复位。因此，LTP在发育中的海马加速突触的发生，而资源依赖性突触的生长和脊柱集群发生在成熟的树突。这种突触内的稳态平衡可塑性被假设为随着老化大脑中认知能力的下降而被破坏。全面分析成熟和衰老过程中的结构突触可塑性被提出作为理解的基础认知能力的终身变化。具体而言，目标是：目标1：评估资源依赖性突触生长和聚类的成熟。目的2：确定电路的一般性和突触的特异性，资源依赖型增长和集群。目的3：确定认知能力的突触基础，衰老的海马体的衰退目的4：测试棘器在突触生长中的重要性，聚类结果承诺对整个生命周期的学习和记忆的突触基础进行必要的深入了解并将提供基础知识，为发展和年龄相关的大脑提供新的治疗方法。紊乱