CRCNS: Computational Characterization of C. Elegans Nociceptive Behavior as a Quantitative Model for Pain Transduction

众所周知，对疼痛的适当反应对所有动物的生存都至关重要，但在开展旨在理解疼痛生物学的研究时存在固有的困难。人类的疼痛研究实际上是困难的，本质上是主观的，并且在伦理上受到限制。非人类动物的疼痛研究是有问题的，因为动物不能有意识地对疼痛进行排序和交流，因此，特别是当使用无脊椎动物模型时，人们必须从表征动物行为的高精度实验中推断疼痛水平。这种分析通常是定性的，不一定反映疼痛行为反应的复杂性和多维性。本项目将利用现代信息理论工具解决多维数据分析和行为建模问题。蛔虫，秀丽隐杆线虫，将作为疼痛研究的模式生物，因为它是遗传易感性的，并提供了高通量，定量，行为表征的机会。蠕虫的行为数据将收集响应伤害性刺激使用定制跟踪显微镜。数据将被拟合到一个计算模型中，该模型将允许根据行为输出预测重建应用的疼痛水平。该模型将滤除蠕虫生理状态的干扰效应。该项目将探索疼痛反应的可靠性和稳健性，并将确定反应的神经元介质。这将是真核生物中刺激诱导的整个生物体行为的第一个全面表征，并将建立在细菌趋化性的开创性工作之上。该项目有望通过在动物模型中实现疼痛转导的客观表征来影响生物医学研究。它将通过专题研讨会促进对感官诱导行为的定量、计算表征的研究和教育，从而影响科学界。它将通过开发与行为定量研究相关的新课程、模块和课程，以及更普遍的定量生物学，进一步影响高中和大学的STEM培训。

It is well established that appropriate responses to pain are essential for the survival of all animals, but there are inherent difficulties in carrying out studies aimed at understanding the biology of pain. Pain research in humans is practically difficult, inherently subjective, and ethically constrained. Pain research in non-human animals is problematic because animals cannot rank and communicate their pain consciously and thus, especially when using invertebrate models, one must infer the pain level from high precision experiments that characterize animal behavior. Such analyses are typically qualitative and not necessarily reflective of the complex and multidimensional nature of pain behavioral responses. This project will solve the multidimensional data analysis and behavioral modeling problem using modern information-theoretic tools. The roundworm, C. elegans, will serve as the model organism for pain studies since it is genetically tractable and offers opportunities for high-throughput, quantitative, behavioral characterization. Worm behavioral data will be collected in response to nociceptive stimuli using a custom tracking microscope. Data will be fitted to a computational model that will allow reconstruction of the applied pain level as predicted from the behavioral output. The model will filter out confounding effects of the worm's physiological state. The project will explore reliability and robustness of the pain response, and it will identify neuronal mediators of the response. This will be the first comprehensive characterization of stimulus induced whole-organism behavior in eukaryotic organisms and will build on pioneering work carried out on bacterial chemotaxis. The project is expected to impact biomedical research by enabling objective characterization of pain transduction in animal models. It will impact the scientific community by promoting research and education on quantitative, computational characterization of sensory induced behaviors using topical workshops. It will further impact STEM training in high schools and colleges by developing new classes, modules, and curricula related to quantitative studies of behavior, and, more generally, to quantitative biology.