Author Summary “Synthetic lethality” in cell biology is an extreme example of the effects of higher order genetic interactions: The simultaneous knockout of two or more individually nonessential genes leads to cell death. We define a neural analog to this concept in relation to the locomotor response to gentle touch in C. elegans . Two or more neurons are synthetic essential if individually they are not required for this behavior, yet their combination is. We employ a network control approach to systematically assess all pairs and triplets of neurons by their effect on body wall muscle controllability, and find that only surprisingly small sets of neurons are synthetic essential. They are highly localized in the nervous system and predicted to affect control over specific sets of muscles. Abstract Synthetic lethality, the finding that the simultaneous knockout of two or more individually nonessential genes leads to cell or organism death, has offered a systematic framework to explore cellular function, and also offered therapeutic applications. Yet the concept lacks its parallel in neuroscience—a systematic knowledge base on the role of double or higher order ablations in the functioning of a neural system. Here, we use the framework of network control to systematically predict the effects of ablating neuron pairs and triplets on the gentle touch response. We find that surprisingly small sets of 58 pairs and 46 triplets can reduce muscle controllability in this context, and that these sets are localized in the nervous system in distinct groups. Further, they lead to highly specific experimentally testable predictions about mechanisms of loss of control, and which muscle cells are expected to experience this loss.

Network neuroscience strives to understand the networks of the brain on all spatiotemporal scales and levels of observation. Current experimental and theoretical capabilities are beginning to facilitate a more holistic perspective, uniting these networks. This focus feature, “Bridging Scales and Levels,” aims to document current research and looks to future progress towards this vision.