Distance-Dependent Structure and Function of Neuronal Dendrites

神经元树突的距离依赖性结构和功能

• 批准号: 8448268
• 负责人: KRISTEN M HARRIS
• 金额: $ 32.09万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448268
• 关键词: Area; Asses; Axon; Brain; Calcium; Caliber; Cell model; Data; Dendrites; Electron Microscopy; Endosomes; Equilibrium; Goals; Golgi Apparatus; Image Analysis; Individual; Knowledge; Learning; Left; Length; Long-Term Potentiation; Measurement; Measures; Membrane Proteins; Memory; Mental Retardation; Microtubules; Mitochondria; Neurons; Pathology; Polyribosomes; Positioning Attribute; Process; Production; Protein Biosynthesis; Recycling; Regulation; Research; Resources; Serum; Smooth Endoplasmic Reticulum; Sorting - Cell Movement; Structure; Subcellular structure; Sum; Synapses; Trees; Variant; Vertebral column; Wit; Work; design; effective therapy; improved; nervous system disorder; novel strategies; protein transport; public health relevance; reconstruction; synaptic function; tomography; tool

DESCRIPTION (provided by applicant): "Distance-Dependent Structure and Function of Neuronal Dendrites" Neuronal dendrites, axons and synapses are structurally distorted in individuals with mental retardation and other neurological disorders. Their structure also differs greatly in normal brains. The overall goal of this research is to characterize this structural variation to learn how neurons regulate, sustain, and alter synaptic connectivity as brain function develops and changes with learning and pathology. The approach is three-dimensional reconstruction and quantification through serial section electron microscopy (EM). Long-term potentiation (LTP), a robust cellular model for learning, is exploited to investigate subcellular components including microtubules for transport; smooth endoplasmic reticulum for calcium regulation and protein trafficking; polyribosomes, Golgi outposts, and spine apparatuses for local protein synthesis; recycling and sorting endosomes for redistribution and degradation of membranes and proteins; and mitochondria for ATP production and calcium regulation. Our new discovery that total synaptic load, measured as summed synaptic area, is evenly balanced along dendrites and scales with caliber, suggests that heterosynaptic competition for intrinsic resources may control how many synapses a dendrite or axon can sustain along its length. Even when synapses enlarge during LTP, the total synaptic load in healthy brains is re-equilibrated by 2 hr, leaving fewer but larger synapses along the potentiated dendrites. Furthermore, only ~20% of the axons that pass next to dendrites actually form synaptic contacts, suggesting that similar intrinsic resource limitations might govern the number and size of synapses supported along axons. A rigorous plan is proposed to assess whether core structures scale with synapse number and size along dendrites of different calibers and positions in the dendritic arbor, and their associated axons during LTP. Novel approaches in EM tomography, large EM field imaging and analysis are being developed to improve the quality of the measurements, increase efficiency, and to share content-rich data broadly.This work is at the forefront of the systematic study of intrinsic mechanisms to control inter-neuronal connectivity and synaptic function.Such knowledge is crucial to design effective treatments for many neurological disorders.

描述（由申请人提供）：“神经元树突的距离依赖性结构和功能”神经元树突、轴突和突触在患有精神发育迟滞和其他神经系统疾病的个体中结构扭曲。 它们的结构在正常大脑中也有很大不同。 这项研究的总体目标是描述这种结构变化，以了解神经元如何调节，维持和改变突触连接，因为大脑功能随着学习和病理学的发展和变化。 该方法是通过连续切片电子显微镜（EM）进行三维重建和定量。 长时程增强（LTP）是一种用于学习的强大细胞模型，用于研究亚细胞组分，包括用于运输的微管;用于钙调节和蛋白质运输的滑面内质网;用于局部蛋白质合成的多聚核糖体，高尔基前哨和脊柱装置;用于膜和蛋白质的再分配和降解的内体的回收和分选;以及用于ATP产生和钙调节的线粒体。 我们的新发现是，总的突触负荷（以突触面积的总和来衡量）是沿着沿着树突均匀平衡的，并且随着管径的变化而变化。这表明，对内在资源的异突触竞争可能控制着树突或轴突沿着其长度沿着可以维持多少突触。 即使突触在LTP期间扩大，健康大脑中的总突触负荷在2小时内重新平衡，沿着增强的树突留下更少但更大的突触。 此外，只有约20%的轴突通过旁边的树突实际上形成突触接触，这表明类似的内在资源限制可能支配突触的数量和大小支持沿着轴突。 提出了一个严格的计划，以评估是否核心结构的规模与突触的数量和大小沿着树突的不同口径和位置的树突乔木，及其相关的轴突在LTP。 新的方法在电磁断层扫描，大电磁场成像和分析正在开发，以提高测量的质量，提高效率，并广泛共享内容丰富的数据。这项工作是在内在机制的系统研究，以控制神经元间的连接和突触功能的前沿。这些知识是至关重要的设计有效的治疗方法，许多神经系统疾病。