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

项目摘要 神经科学中的一个核心问题是神经在开发过程中如何自我组织到功能 结构。神经回路功能依赖于突触的精确规范，而突触的改变 连通性与许多神经发育障碍有关。开创性研究已经确定 改变大脑接线的突变和分子机制。但是，这些遗传信息最终如何领导 自我组装神经回路的理解很少。哪些发展计划导致功能性 神经元结构？哪些规则描述了这些程序？细胞如何实施这些规则？ 果蝇视觉系统代表了电路自组装问题的一个非凡实例 发展大脑。复合眼（由〜800子）通过“神经原则”连接 叠加”（NSP）：800倍六个光感受器，看到相同的空间点，但原始 不同的Ommatidia，在薄片中互相找到彼此，并在突触墨盒中“一起”。正确的排序 光感受器生长锥的生长锥导致光收集敏感性增加了六倍，而没有空间 解决。但是，鲜为人知的是，有4800个伸长生长锥在目标墨盒上停止 惊人的精度大于99％。 在初步研究中，我们确定了基于多光子的非侵入性现场成像的能力 完整和正常发育p pa的显微镜检查在测定光感受器生长锥动力学过程中的显微镜 NSP。使用这种方法，我们获得了单个生长锥体动力学的第一个定量测量 在整个NSP过程中，确定NSP的复杂程序可能来自三个 简单的当地规则，该规则控制着生长锥锚，在薄片中延长和停止。我们的工作 提出了以下假设：停止接线的蜂窝决定可能是由集体互动引起的 相邻细胞，这些相互作用可以缓冲生物学变化，例如 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）实验 确定生长锥前，背部和靶细胞的潜在时间和地点 相互影响; （目标2）使用这些数据来限制系统比较不同的计算模型 停止规则的模型； （目标3）实验搜索NSP接线错误传播的签名 突变条件并确定参与实施停止规则的分子成分。 1