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至关重要，但开展旨在了解疼痛生物学的研究存在固有的困难。人类的疼痛研究实际上是困难的，本质上是主观的，而且受到伦理的限制。在非人类动物中进行疼痛研究是有问题的，因为动物不能有意识地对它们的疼痛进行排名和交流，因此，特别是在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和多维性质。该项目将利用现代信息论工具解决多维数据分析和行为建模问题。线虫将作为疼痛研究的模式生物，因为它在基因上是可驯化的，并为高通量、定量和行为表征提供了机会。将使用定制跟踪显微镜收集蠕虫行为数据，以响应伤害性刺激。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的应用疼痛程度的重建。该模型将过滤掉蠕虫生理状态的混杂影响。该项目将探索疼痛反应的可靠性和健壮性，并将确定该反应的神经元介体。这将是对真核生物中刺激诱导的整个有机体行为的第一个全面表征，并将建立在细菌趋化性方面开展的开创性工作的基础上。该项目预计将通过在动物模型中客观描述疼痛传导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量化、计算表征的研究和教育，从而影响科学界。它将通过开发新的课程、模块和课程来进一步影响高中和大学的STEM培训，这些课程、模块和课程与行为的定量研究有关，更广泛地讲，与定量生物学有关。

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.