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

基本信息

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
项目类别：
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

项目摘要

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神经回路功能依赖于突触的精确规范，而突触的改变。开创性研究已发现连通性与许多神经发育障碍有关。然而，这种遗传信息最终如何导致改变大脑线路的突变和分子机制。对于神经回路的自组装是由什么发育程序导致功能性的，人们知之甚少。神经结构？什么规则描述了这些程序？果蝇视觉系统代表了电路自组装问题的一个显着例子。发育中的大脑（由约 800 个小眼组成）通过“神经原理”连接。叠加”（NSP）：800 乘以六个感光器，它们看到空间中的同一点，但源自六个不同的小眼，在椎板中找到彼此，并在突触盒中“连接在一起”。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使用这种方法，我们首次获得了个体生长锥动力学的定量测量结果。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，控制着生长锥如何在椎板中锚定、伸长和停止。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，例如不完美的方向为了研究 NSP 期间的集体停止决策，我们将：（目标 1）通过实验进行。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交互；（目标 2）使用这些数据来约束系统地比较不同的计算模型停止规则模型；以及（目标 3）通过实验寻找 NSP 接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