Reverse-engineering mechanisms of neural circuit wiring in the fly visual system

果蝇视觉系统中神经回路布线的逆向工程机制

• 批准号: 9363666
• 负责人: STEVEN J ALTSCHULER
• 金额: $ 37.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363666
• 关键词: Back; Biological; Biological Assay; Brain; Buffers; Cell Communication; Cells; Complex; Computer Simulation; Computing Methodologies; Cues; Data; Decision Making; Development; Disease; Drosophila genus; Engineering; Eye; Feedback; Future; Genetic; Goals; Growth Cones; Human; Image; Individual; Instruction; Lead; Learning; Light; Mathematics; Measurement; Microscopy; Modeling; Molecular; Mosaicism; Mutation; Nerve Regeneration; Neurodevelopmental Disorder; Neurons; Neurosciences; Pattern; Photoreceptors; Play; Process; Pupa; Resolution; Retina; Role; Seminal; Signal Transduction; Sorting - Cell Movement; Stereotyping; Structure; Synapses; System; Time; Variant; Visual; Visual Fields; Visual system structure; Work; base; cellular engineering; compound eye; computer studies; crystallinity; design; fly; genetic information; in vivo; insight; intravital imaging; multi-photon; mutant; neural circuit; neural model; neuromechanism; neuron development; postsynaptic; presynaptic; programs; quorum sensing; relating to nervous system; repaired; self assembly; visual map

Project Summary A central question in neuroscience is how neural circuits self-organize during development into functional structures. Neural circuit function relies on the precise specification of synapses, while alterations of synaptic connectivity are associated with numerous neurodevelopmental disorders. Seminal studies have identified mutations and molecular mechanisms that alter brain wiring. Yet, how this genetic information ultimately leads to self-assembly of neural circuits is poorly understood. What developmental programs lead to functional neuronal structures? What rules describe these programs? How do cells implement these rules? The Drosophila visual system represents a remarkable instance of the circuit self-assembly problem in the developing brain. The compound eye (consisting of ~800 ommatidia) is wired through a principle of “neural superposition” (NSP): 800 times six photoreceptors that see the same point in space, yet originate from six different ommatidia, find each other in the lamina and ‘wire together’ in synaptic cartridges. The correct sorting of photoreceptor growth cones results in a six-fold increase in light-gathering sensitivity without loss of spatial resolution. However, it is poorly understood how 4800 elongating growth cones stop at target cartridges with an astonishing accuracy of greater than 99%. In preliminary studies, we established the ability to use non-invasive, live-imaging based on multi-photon microscopy of intact and normally developing pupae to assay photoreceptor growth cone dynamics during NSP. Using this approach, we obtained the first quantitative measurements of individual growth cone dynamics throughout the entire NSP process and established that the complex program of NSP could arise from three simple local rules, which govern how growth cones anchor, elongate and stop in the lamina. Our work suggested the hypothesis that a cellular decision to stop wiring could arise from collective interactions with neighboring cells, and that these interactions could buffer biological variation, such as imperfect direction of growth cone elongation. To investigate collective stop decisions during NSP, we will: (Aim 1) experimentally determine potential times and places where growth cone fronts, backs and target cells could physically interact; (Aim 2) use these data to constrain computational models that systematically compare different models of stop rules; and (Aim 3) experimentally search for signatures of error propagation of NSP wiring in mutant conditions and identify molecular components that participate in the implementing the stop rule. 1

项目概要 神经科学的一个中心问题是神经回路在发育成功能性过程中如何自组织 结构。神经回路功能依赖于突触的精确规范，而突触的改变 连接性与许多神经发育障碍有关。开创性研究已经确定 改变大脑线路的突变和分子机制。然而，这种遗传信息最终如何导致 人们对神经回路的自组装知之甚少。哪些发展计划会带来功能性的发展 神经元结构？这些程序有哪些规则？细胞如何执行这些规则？ 果蝇视觉系统代表了电路自组装问题的一个显着例子。 正在发育的大脑。复眼（由约 800 个小眼组成）通过“神经 叠加”（NSP）：800 乘以 6 个光感受器，看到空间中的同一点，但源自 6 个光感受器 不同的小眼在椎板中找到彼此，并在突触盒中“连接在一起”。正确的排序 光感受器生长锥的增加导致聚光灵敏度增加六倍，而不会损失空间 解决。然而，人们对 4800 个伸长的生长锥如何在目标盒上停止的了解甚少。 超过 99% 的惊人准确率。 在初步研究中，我们建立了使用基于多光子的非侵入性实时成像的能力 完整和正常发育的蛹的显微镜检查，以测定光感受器生长锥动态 国家标准局。使用这种方法，我们获得了个体生长锥动力学的第一个定量测量 贯穿整个 NSP 过程，并确定 NSP 的复杂程序可能来自三个方面 简单的局部规则，控制生长锥如何在椎板中锚定、伸长和停止。我们的工作 提出了这样的假设：细胞停止布线的决定可能是由与 邻近细胞，并且这些相互作用可以缓冲生物变化，例如不完美的方向 生长锥伸长。为了调查 NSP 期间的集体停止决策，我们将：（目标 1）通过实验 确定生长锥正面、背面和目标细胞可以物理生长的潜在时间和地点 相互影响; （目标 2）使用这些数据来约束计算模型，系统地比较不同的 停止规则模型； (目标 3) 通过实验寻找 NSP 布线的错误传播特征 突变条件并识别参与实施停止规则的分子成分。 1