CAREER: From Connectome to Behavior: Computational Models of Multifunctional Neural Circuits in C. elegans

动物如何作为一个凝聚力单位灵活地协调多种行为是神经科学的核心问题之一；多功能也被认为是发展一般人工智能的根本挑战之一。尽管神经回路的灵活重组能力在生物体中广泛存在，但大多数关于行为的神经基础的研究都集中在孤立的回路和个体行为上。考虑多功能电路的研究往往集中在不同活动模式之间的切换，而对多功能感觉运动整合的洞察很少。随着越来越多的解剖学、生理学和行为学数据的产生，理解行为的神经基础的计算建模框架是必不可少的。这个项目的目标是对已经被孤立识别的多个神经回路进行建模，并将它们集成到一个模型中，以更好地理解感觉驱动的行为回路中的多功能是如何产生的。该项目是朝着在单个神经元水平上开发活体的行为-功能脑-身体-环境模型这一长期目标迈出的重要一步。从该项目开发的跨学科方法将成为理解活体中多功能电路以及产生能够稳健和有效地执行多种功能的人工系统的跳板。该项目特别侧重于对线虫线虫的各种空间定向行为的电路进行建模和分析。这种模式生物体是对完整动物进行集成计算建模的唯一合格目标，因为它的遗传学、发育、解剖学和行为的信息广度已知。尽管有这些丰富的知识，但关于其神经系统的电生理特性的信息还不够完整。该项目旨在通过对生物体的解剖学和生理学的已知知识来约束该模型，并对其身体和环境进行合理的简化。然后，随机优化将被用来填充电生理未知数，以便模型产生与已观察到的行为相匹配的行为，包括神经操作对行为的影响。优化的结果将不是唯一的模型，而是与系统当前知识一致的模型的集合。这些可能性中的每一种都代表着线虫的一个可验证的假说。该项目的下一步将是分析这个集合的结构，以制定关键实验，以区分蠕虫中的各种可能性。然后，这些实验的结果可以用作在模型精化的迭代周期中的后续优化的附加约束。除了产生特定于线虫的可实验验证的预测外，通过对模型集合的分析，该项目旨在更广泛地发现多功能电路如何在生物体中运行的一般原理。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

How an animal flexibly coordinates multiple behaviors as a cohesive unit is one of the central problems of neuroscience; multifunctionality has also been recognized as one of the fundamental challenges in the development of a general artificial intelligence. Although the ability of neural circuits to flexibly reconfigure is widespread among organisms, most studies of the neural basis of behaviors focus on isolated circuits and individual behaviors. Studies that consider multifunctional circuitry tend to focus on the switching between distinct patterns of activity, with little insight into multifunctional sensorimotor integration. With the increasing amount of anatomical, physiological and behavioral data being generated, a computational modeling framework to understand the neural basis of behavior is essential. The goal of this project is to model multiple neural circuits that have been identified in isolation and to integrate them into a single model to better understand how multifunctionality arises in sensory-driven behavioral circuits. This project is an important step toward the long-term goal of developing a behaviorally-functional brain-body-environment model of a living organism at the level of individual neurons. The cross-disciplinary methodologies developed from this project will serve as a springboard for understanding multifunctional circuits in living organisms as well as for generating artificial systems capable of robustly and efficiently performing multiple functions. The project focuses specifically on modeling and analyzing the circuits responsible for the wide range of spatial orientation behaviors in the nematode Caenorhabditis elegans. This model organism is a uniquely qualified target for integrated computational modeling of a complete animal because of the breadth of information known about its genetics, development, anatomy, and behavior. Despite this substantial knowledge, information about the electrophysiological properties of its nervous system is less complete. The project aims to constrain the model by what is known from the anatomy and physiology of the organism with reasoned simplifications about its body and environment. Then, stochastic optimization will be used to fill in electrophysiological unknowns such that the model produces behavior that matches what has been observed, including the effect of neural manipulations on behavior. The result of optimization will not be a unique model, but rather an ensemble of models that are consistent with current knowledge of the system. Each of these possibilities represents a testable hypothesis for C. elegans. The next step in the project will be to analyze the structure of this ensemble to formulate the key experiments that can distinguish between the various classes of possibilities in the worm. The results of such experiments can then be used as additional constraints for subsequent optimizations in an iterative cycle of model refinement. Besides the generation of experimentally-testable predictions that are specific to C. elegans, through the analysis of the ensemble of models, the project aims to discover general principles for how multifunctional circuits operate in living organisms more broadly.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.