Connecting a Connectome to Behavior: An Ensemble of Neuroanatomical Models of C. elegans Klinotaxis

Increased efforts in the assembly and analysis of connectome data are providing new insights into the principles underlying the connectivity of neural circuits. However, despite these considerable advances in connectomics, neuroanatomical data must be integrated with neurophysiological and behavioral data in order to obtain a complete picture of neural function. Due to its nearly complete wiring diagram and large behavioral repertoire, the nematode worm Caenorhaditis elegans is an ideal organism in which to explore in detail this link between neural connectivity and behavior. In this paper, we develop a neuroanatomically-grounded model of salt klinotaxis, a form of chemotaxis in which changes in orientation are directed towards the source through gradual continual adjustments. We identify a minimal klinotaxis circuit by systematically searching the C. elegans connectome for pathways linking chemosensory neurons to neck motor neurons, and prune the resulting network based on both experimental considerations and several simplifying assumptions. We then use an evolutionary algorithm to find possible values for the unknown electrophsyiological parameters in the network such that the behavioral performance of the entire model is optimized to match that of the animal. Multiple runs of the evolutionary algorithm produce an ensemble of such models. We analyze in some detail the mechanisms by which one of the best evolved circuits operates and characterize the similarities and differences between this mechanism and other solutions in the ensemble. Finally, we propose a series of experiments to determine which of these alternatives the worm may be using. Maps of the connections between neurons are being assembled for several organisms, including humans. But connectivity alone is insufficient for understanding the mechanisms of behavior. Nowhere is this more obvious than in the nematode C. elegans, where the nearly complete connectome has been available for over 25 years yet little is known about the neural basis of most of its behavior. Here we combine known neuroanatomical constraints from the C. elegans connectome with a simplified body and environment, and use optimization techniques to fill in the missing electrophysiological parameters in plausible ways so as to produce worm-like behavior. We focus on one spatial orientation behavior, where the reactions to sensory input depend on the worm's internal state at the time of the stimulus: salt klinotaxis. By exploring the possibilities for what is unknown in ways that are consistent with what is known, we generate an ensemble of hypotheses about the neural basis of this behavior. Studying the structure of this ensemble, we formulate new experiments that can distinguish between the various hypotheses. This methodology is likely to accelerate the discovery and understanding of the biological circuitry underlying the behavior of interest, before a complete electrophysiological characterization is available.