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Abstract

How did nervous system signaling evolve? Recent advances in high- throughput technologies are now allowing us to address this question through largescale studies of animal nervous systems. Connectomics is the reconstruction of an organism‘s neural circuits based on synaptic connections between neurons. This approach enables the generation of maps of information flow through the nervous system that can provide mechanistic explanations of an organism‘s behavior. However, connec- tome maps based on synaptic connectivity alone give an incomplete understanding of nervous system function, as they fail to provide details of the signaling molecules involved in communication between different neurons. By combining connectome data with information from spatially resolved single cell RNA-Seq and high-throughput matching of signaling molecules to their specific receptors, we can incorporate details of mole- cular signaling into synaptic connectivity maps. Here, I demonstrate this approach using the larvae of the marine worm, Platynereis dumerilii, to create maps of chemical connectivity. Mapping the chemical connecto- me provides further insights into different signaling mechanisms ope- rating in the nervous system of the larva, such as combinatorial pepti- dergic signaling and neuronal autoregulation. We used calcium imaging of live larvae to test hypotheses of nervous system signaling generated through the chemical connectome to demonstrate the predictive power of this approach. The addition of chemical neuromodulatory maps to synaptic connectivity maps should lead us to a more holistic understan- ding of the animal nervous system. The Platynereis dumerilii chemical connectome, which incorporates several evolutionarily conserved neuro- nal signaling molecules, will provide an important framework for future comparative studies.