Synapse Elimination during Development: Pruning Rates, Models, and Diseases

发育过程中的突触消除：修剪率、模型和疾病

• 批准号: 8527041
• 负责人: Saket Navlakha
• 金额: $ 5.22万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2015-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527041
• 关键词: Adult; Affect; Algorithms; Animals; Attention; Biological; Biological Neural Networks; Brain; Brain region; Cells; Computer Simulation; Data; Development; Developmental Process; Diagnosis; Disease; Disease model; Drug Targeting; Early Diagnosis; Early treatment; Electron Microscopy; Environment; Feedback; Fragile X Syndrome; Image; Joints; Lead; Link; Machine Learning; Metabolic; Modeling; Mus; Mutant Strains Mice; Neurodevelopmental Disorder; Neurologic; Neurons; Onset of illness; Organism; Plastics; Preparation; Procedures; Process; Property; Research; Rett Syndrome; Solutions; Somatosensory Cortex; Staging; Staining method; Stains; Synapses; Techniques; Telecommunication Network; Testing; Time; Tissues; Vertebral column; barrel cortex; base; computational network modeling; computerized data processing; cost; critical developmental period; critical period; density; design; experience; flexibility; image processing; information processing; insight; meetings; mouse development; mouse model; nervous system disorder; neural circuit; public health relevance; research study; statistics; synaptogenesis; wireless network

DESCRIPTION (provided by applicant): Many neural circuits are formed using a two-stage developmental process that includes an initial period of exuberant synapse formation, followed by a longer period of activity-dependent synapse elimination. While pruning has been well-documented in many organisms and brain regions, little attention has been paid to the rate at which synapses are eliminated during development. Different pruning rates have a strong effect on the quality and plasticity of the resulting neural circuits, and indeed, many neurological diseases have been linked to abnormal synapse levels in the cortex during critical developmental periods. We hypothesize that pruning rates in the cortex have been optimized to achieve both connectivity and robustness of underlying neural circuits. To test our hypothesis, we propose a joint experimental-computational research plan to explore how synapse levels change during development and how these changes manifest at the network and phenotypic levels. First, we will quantify the precise rate of synapse elimination during development of the mouse barrel cortex using a specialized electron microscopy (EM) preparation that selectively stains for synapses. We will develop a fully-automated and high-throughput image processing pipeline that will allow us to count tens of thousands of synapses per time point and gain robust statistics of pruning rates and the time of peak synapse density. Second, we will develop computational models of synaptic pruning to evaluate how pruning rates affect information processing in neural circuits. Our computational experiments will explore how sparse circuits emerge that are capable of efficient and robust encoding, while still being flexible enough for plasticity and adaptation and while meeting metabolic costs. Our models will also help us answer questions about global neural circuitry, including whether hubs are likely to exist and how functional modules are formed. Third, we will examine cases of synapse rewiring and reorganization following abnormal developmental conditions. We will repeat our EM procedure using mouse models of Fragile X syndrome and Rett syndrome to compare synapse levels with respect to control, and we will extend our computational models to understand circuit-level differences in these conditions. The proposed project will generate new computational and experimental solutions for analyzing network development and will lead to biological insights into how local pruning mechanisms affect global circuit properties.

描述（由申请人提供）：许多神经回路是使用两个阶段的发育过程形成的，该过程包括旺盛突触形成的初始时期，随后是较长的活动依赖性突触消除。虽然在许多生物和大脑区域中，修剪已经有充分的文献记录，但在开发过程中消除了突触的速度几乎没有关注。不同的修剪率对产生的神经回路的质量和可塑性具有很强的影响，实际上，许多神经系统疾病与关键发育期间皮质中的突触水平异常有关。 我们假设皮质中的修剪率已被优化，以达到潜在的神经回路的连通性和鲁棒性。为了检验我们的假设，我们提出了一项联合实验性计算研究计划，以探讨突触水平在发育过程中的变化以及这些变化如何在网络和表型水平上表现出来。首先，我们将使用专门的电子显微镜（EM）制剂来量化小鼠桶皮层开发过程中的精确突触消除速率，该制剂有选择地染色突触。我们将开发一个完全自动化的高通量图像处理管道，这将使我们能够计算每个时间点的数以万计的突触，并获得稳健的修剪率和峰值突触密度的时间。其次，我们将开发突触修剪的计算模型，以评估修剪率如何影响神经回路中的信息处理。我们的计算实验将探讨稀疏电路的出现，这些电路能够有效，稳健地编码，同时仍然足够灵活，以实现可塑性和适应性，并在满足代谢成本的同时。我们的模型还将帮助我们回答有关全球神经电路的问题，包括枢纽是否可能存在以及如何形成功能模块。第三，我们将在异常发育条件下检查突触重新布线和重组的案例。我们将使用脆弱X综合征和RETT综合征的小鼠模型重复我们的EM程序，以比较对照的突触水平，我们将扩展计算模型以了解这些条件下电路级别的差异。 拟议的项目将生成新的计算和实验解决方案，以分析网络开发，并将导致对局部修剪机制如何影响全球电路特性的生物学见解。