The C. elegans locomotion nervous system: an integrated multi-disciplinary approach

秀丽隐杆线虫是动物界最简单的生物之一。有了已绘制的基因组和唯一已绘制的神经回路，这种生物提供了第一个切实的机会，让我们能够自下而上和自上而下地了解整个生命、行为和学习系统。因此，它为系统生物学家、神经科学家和机器人学家提供了巨大的希望。尽管相对简单，秀丽隐杆线虫拥有许多属于高级生物的功能，包括进食、交配、复杂的感觉能力、记忆和学习。我们能理解让这种微小的线虫生存和繁衍的潜在工程设计吗？对于产生适应性强、健壮的生命形式或其神经系统独特结构的普遍原理，我们能获得什么样的见解？应对这一挑战需要多学科的努力，结合生物学、物理学、工程学和计算机科学的见解和专业知识。本研究的重点是实现我们对秀丽隐杆线虫运动系统及其神经控制的理解的一个步骤变化。在建模层面，目前秀丽隐杆线虫运动子系统的理论模型依赖于基因组数据、已知的神经回路、有限的秀丽隐杆线虫行为和电生理实验以及其他相关物种的知识。总而言之，这一建模壮举的知识基础非常不完整，因此迄今为止所有的模型都做出了大量未经证实的假设。一些非常基本的问题，例如运动系统是否依赖于中枢模式生成形式的内源性控制，最近一直备受争议。这些问题可以在数学和仿真模型中解决；然而，物理环境（压力、摩擦、感官输入）可能过于复杂，无法可靠地纳入模型。我建议构建线虫的机器人模型，结合神经元回路的替代预测模型，并在各种物理条件下进行测试，模拟生物蠕虫的行为实验。该项目涉及三个层面的调查：首先，对蠕虫运动的系统行为研究；第二，详细的运动系统神经计算模型的构建、分析和仿真；第三，机器人模型的构建和测试。在技术层面上，由于线虫的机械特性，电生理学家一直无法探测秀丽隐杆线虫的神经元和肌肉的活动。因此，尽管取得了一些进展，但确认或进一步发展神经元子系统（如运动子系统）的模型是非常困难的。同时，秀丽隐杆线虫是透明的，因此可以进行荧光记录。人们正在努力开发用于感觉神经元的电压敏感染料，但到目前为止，秀丽隐杆线虫的神经元或肌肉细胞还没有荧光记录。我建议开发分子电压探针来直接记录秀丽隐杆线虫运动肌肉的电压活动。这项工作建立在我将量子点（半导体纳米粒子）嵌入生物膜的初步工作的基础上。接下来的步骤包括从这些探针获得电压响应，并将它们嵌入活体动物的细胞中。监测行为动物的电压活动的能力将导致我们对运动系统特别是秀丽隐杆线虫运动系统的理解发生重大变化。此外，这项技术的实施将构成一个重大的进步，远远超出秀丽隐杆线虫的研究，在生物和生物启发工程领域广泛的科学和工业应用。

C. elegans is one of the simplest creatures of the animal kingdom. With a mapped genome and the only mapped neural circuitry, this organism offers a first tangible opportunity to understand an entire living, behaving and learning system bottom-up and top-down. As such, it offers great promise to systems biologists, neuroscientists and roboticists alike. Despite its relative simplicity, C. elegans possesses many of the functions that are attributed to higher level organisms, including feeding, mating, complex sensory abilities, memory and learning. Can we understand the underlying engineering designs that allow this tiny nematode to survive and flourish? What insight can we gain into universal principles that give rise to adaptive and robust life-forms or to the unique architecture of its nervous system? Meeting this challenge requires a large multi-disciplinary effort, combining insight and expertise from biology, physics, engineering and computer science.The proposed research focuses on achieving a step change in our understanding of the C. elegans locomotion system and its neural control. At the modelling level, current theoretical models of the locomotion subsystem of C. elegans rely on genomic data, the known neural circuitry, limited behavioural and electrophysiological experiments on C. elegans and knowledge from other related species. All in all the knowledge base for this modelling feat is very incomplete and hence all models to date make a large number of unconfirmed assumptions. Very fundamental questions, such as whether the locomotion system relies on endogenous control in the form of central pattern generation, have recently been debated. These questions can be addressed in mathematical and simulation models; however, the physical environment (pressure, friction, sensory inputs) may be too complex to incorporate reliably in a model. I propose to construct robotic models of the nematode, incorporating alternative predicted models of neuronal circuits and to test them under a variety of physical conditions, mimicking behavioural experiments on the biological worm. This project involves three levels of investigation: First, systematic behavioural studies of the locomotion of the worm; second, the construction, analysis and simulation of detailed neurocomputational models of the locomotion system; and third, the construction of robotic models and their testing.At the technological level, probing the activity of C. elegans neurons and muscles has eluded electrophysiogists due to the mechanical properties of the worm. Hence, despite some progress, it is remarkably difficult to confirm or further develop models of neuronal subsystems such as the locomotion subsystem. At the same time, C. elegans is transparent and hence amenable to fluorescence recordings. Efforts are underway to develop voltage-sensitive dyes for sensory neurons, but to date, C. elegans neurons or muscle cells have not been fluorescently recorded from. I propose to develop molecular voltage probes to directly record the voltage-activity of C. elegans locomotion muscles. This effort builds on my preliminary work in which quantum dots (semiconductor nanoparticles) have been embedded in biological membranes. The next steps involve obtaining a voltage-response from these probes and embedding them in cells of living animals. The ability to monitor the voltage activity in behaving animals should lead to a step change in our understanding of the locomotion system in particular and the C. elegans motor system in general. Furthermore, implementation of this technology should constitute a major advance that extends much beyond the study of C. elegans to a wide range of scientific and industrial applications in both biological and bioinspired engineering domains.