Synaptic plasticity across the lifespan

整个生命周期的突触可塑性

• 批准号: 10426173
• 负责人: KRISTEN M HARRIS
• 金额: $ 57.52万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 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/10426173
• 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; 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; postnatal; postsynaptic; presynaptic; reconstruction; response; senescence; synaptogenesis; synaptopodin; young adult

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) 是一个非常适合研究这些过程的学习和记忆模型。树突棘寄主大约 大脑中90%的兴奋性突触，众所周知，在以下情况下显示出结构可塑性 LTP的诱导。树突棘的发育期与突发性发育期相吻合 出生后第12天(P12)大鼠海马区持续3小时以上的LTP(L-LTP)。在P10和P15，LTP 促进突触形成和小脊椎的形成。随着成熟，LTP加速的突触发生 转变为扩大特定突触并在局部保留脊束，但通过缩小保持平衡的过程 在树突上其他地方的脊椎数量上。脊椎群集由Smooth的可用性在本地进行界定 内质网(SER)是调节钙、脂类和蛋白质运输的关键细胞器， 以及多聚核糖体的存在，这些多核糖体介导了局部蛋白质的合成。LTP产生的突触 在含有脊柱器官的脊柱上放大最大，脊柱器官是一种源自SER的结构， 提供跨膜蛋白的合成和翻译后修饰。中国的结构性变化 突触前轴突在LTP后也受到发育调节，并反映出新的 15岁时形成的牛顿适应LTP加速的突触发生，出现的牛顿较少 60岁时脊柱复位术。因此，发育中的海马中的LTP加速了突触的形成，而资源依赖的突触生长和脊椎聚集发生在成熟的树突上。突触中的这种动态平衡 可塑性被认为是随着大脑老化认知能力的下降而被打乱的。综合分析 成熟和衰老期间的结构突触可塑性被认为是理解的基础 认知能力的终生变化。具体地说，目标是：目标1：评估资源依赖型突触生长和聚集的成熟度。目的2：确定脑电活动的电路共性和突触特异性 资源依赖型增长和集群化。目的3：确定认知能力的突触基础 老化的海马体衰退。目的4：测试脊柱结构在突触生长和发育中的重要性 集群化。结果预示着对一生中学习和记忆的突触基础的基本洞察 并将提供基本知识，为发育和年龄相关的大脑提供新的治疗方法 精神错乱。