Synaptic plasticity across the lifespan

整个生命周期的突触可塑性

基本信息

批准号：
10192834
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192834
关键词：
3-Dimensional ARHGEF5 gene 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 (Brain)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 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 Structure of molecular layer of cerebellar cortex 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 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（LTP）是一种非常适合研究这些过程的学习和记忆模型。树突棘承载着大脑中百分之九十的兴奋性突触，众所周知，在以下情况下表现出结构可塑性 LTP的诱导。树突棘的发育起始与树突棘的突然发育起始相一致出生后第 12 天 (P12) 大鼠海马的 LTP 持续超过 3 小时 (L-LTP)。在 P10 和 P15 处，LTP 增强突触发生和小棘的形成。随着成熟，LTP 加速突触发生转变为扩大特定突触并局部保留脊柱簇的过程，但通过减少来平衡树突其他地方的脊柱数量。脊椎簇由平滑的可用性局部界定内质网（SER）是调节钙、脂质和蛋白质运输的关键细胞器，以及介导局部蛋白质合成的多核糖体的存在。 LTP 产生的突触包含脊柱装置的脊柱增大程度最大，脊柱装置是源自 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，并反映了新的脊柱变化形成的 boutons 是为了适应 P15 处 LTP 加速的突触发生，并且发生的 boutons 更少 P60 处脊柱复位。因此，发育中的海马体中的 LTP 加速了突触发生，而资源依赖性突触生长和棘簇发生在成熟的树突上。突触中的这种稳态平衡据推测，衰老大脑的认知能力下降会破坏可塑性。综合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生变化。具体来说，目标是：目标 1：评估资源依赖型突触生长和聚类的成熟度。目标 2：确定电路的通用性和突触特异性资源依赖型增长和集群。目标 3：确定认知能力和突触基础老化的海马体衰退。目标 4：测试脊柱装置在突触生长和发育中的重要性聚类。结果有望深入了解整个生命周期学习和记忆的突触基础并将提供基础知识，为发育性和与年龄相关的大脑的新疗法提供信息失调。