Distance-Dependent Structure and Function of Neuronal Dendrites

描述(申请人提供)：“神经树突的距离依赖的结构和功能”神经树突、轴突和突触在精神发育迟滞和其他神经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的不同。本研究的总体目标是表征这种结构变化，以了解神经元如何随着大脑功能的发展和学习和病理的发展而调节、维持和改变突触连接。该方法是通过连续切片电子显微镜(EM)进行三维重建和量化。长时程增强(LTP)是一种强大的学习细胞模型，它被用来研究亚细胞成分，包括用于运输的微管；用于钙调节和蛋白质运输的光滑内质网；用于局部蛋白质合成的多核糖体、高尔基前哨和脊器；用于膜和蛋白质的再分配和降解的内吞体的循环和分选；以及用于ATP生产和钙调节的线粒体。我们的新发现表明，突触总负荷(以突触总面积衡量)在树突上是均匀平衡的，并随着口径的扩大而扩大，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其长度可以维持多少突触。即使当突触在LTP期间扩大时，健康大脑中的总突触负载在2小时后重新平衡，沿着增强的树突留下更少但更大的突触。此外，只有约20%经过树突旁边的轴突实际上形成了突触接触，这表明类似的固有资源限制可能控制着轴突支持的突触的数量和大小。提出了一个严格的计划，以评估在LTP过程中，核心结构是否随着突触数量和大小沿着树突中不同口径和位置的树突及其相关轴突而缩放。在电磁断层扫描、大电磁场成像和分析方面，人们正在开发新的方法，以改善测量质量，提高效率，并广泛共享内容丰富的数据。这项工作处于系统研究控制神经元间连接和突触功能的内在机制的前沿。这些知识对于设计有效的神经疾病治疗方案至关重要。

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.