RI: Small: An Ensemble of Neuromechanical Models of C. elegans Locomotion

神经科学的核心挑战之一是理解动物是如何作为整体运作的，也就是说，它们的神经活动如何与它们的身体和环境的特性相协调，从而协调它们的行为。当面临如此艰巨的挑战时，首先研究感兴趣的一般问题的较简单实例是有意义的。在这方面，线虫秀丽线虫是研究大脑-身体-环境综合系统运行的唯一合格的目标。它是唯一一种已知其整个神经系统连接的动物。事实上，它整个身体的解剖结构已经被表征为单个细胞的水平。此外，它的基因组已经完全测序，从受精卵到成年动物的整个发育谱系都得到了表征。这个项目的目标是利用这些资源来构建线虫运动的大脑-身体-环境综合模型，这一行为是这种动物表现出的所有其他行为的基础。尽管线虫的整个连接体是已知的，但对其神经系统的电生理学的详细知识还远远不完整。为此，该方法包括两个部分：约束随机优化和集成分析。研究人员将构建受线虫腹索电路已知连通性、其体壁肌肉系统的已知布局以及所涉及的神经元的部分电生理特性的约束的计算模型。然后，他们将应用随机优化技术(进化算法)，以找到该模型的未知电生理参数值，从而最大化运动性能的衡量标准。一般来说，不同的优化会导致这些参数的不同值，所有这些值都与已知的实验约束一致。因此，研究对象不是一个单独的模型，而是反复优化产生的整个模型集合。对这一整体的详细研究将提出具体的新实验，其结果可用于进一步限制未来的优化。这些建模工作的重点是了解来自身体伸展感受器的本体感觉反馈和腹索回路的内在动力学在运动模式的产生和传播中所起的相对作用。

One of the central challenges of neuroscience is understanding how animals operate as integrated wholes, that is, how their neural activity, working in concert with the properties of their bodies and environments, coordinates their behavior. When faced with such a daunting challenge, it makes sense to first study simpler instances of the general problem of interest. In this regard, the nematode worm Caenorhabditis elegans is a uniquely qualified target for investigating the operation of integrated brain-body-environment systems. It is the only animal for which the connectivity of its entire nervous system is known. In fact, the anatomical structure of its entire body has been characterized to the level of individual cells. In addition, its genome has been completely sequenced and its entire developmental lineage has been characterized, from fertilized egg to adult animal. The goal of this project is to draw upon these many resources in order to construct integrated brain-body-environment models of C. elegans locomotion, a behavior that serves as the foundation for all other behaviors that this animal exhibits.Although the entire connectome of C. elegans is known, detailed knowledge of the electrophysiology of its nervous system is far less complete. For this reason, the approach has two components: constrained stochastic optimization and ensemble analysis. The investigators will construct computational models constrained by the known connectivity of the C. elegans ventral cord circuitry, the known layout of its body wall musculature and the partially-known electrophysiological properties of the neurons involved. They will then apply a stochastic optimization technique (evolutionary algorithms) in order to find values of the unknown electrophysiological parameters of this model that maximize a measure of locomotion performance. In general, different optimizations will result in different values for these parameters, all of which are consistent with the known experimental constraints. Thus, the object of study is not an individual model, but rather the entire ensemble of models that result from repeated optimizations. A detailed study of this ensemble will suggest specific new experiments whose results can then be used to further constrain future optimizations. The particular focus of these modeling efforts is on understanding the relative roles that proprioceptive feedback from body stretch receptors and the intrinsic dynamics of ventral cord circuitry play in the generation and propagation of the locomotion pattern.