Reengineering the Nervous System of a Cnidarian

Our goal is to 'break the code' of the nervous system of the small freshwater cnidarian Hydra vulgaris and reverse-engineer its neural control systems, in order to design novel behaviors and recode them into its nervous system by reprogramming it. In a first stage we will decipher the neural code that relates the patterns of spikes to different behaviors. Specifically, we will use calcium imaging to record the activity of all of Hydra’s neurons and muscles during oscillatory contractions, elongations and food egestion. In parallel, our collaborators will use connectomics to perform the ultrastructural mapping of the entire nervous system. With the wiring diagram and the map of all the neuronal and muscle activity we will build bottom-up network and control theory models of the nervous system, musculature and behavior and validate them using two-photon optogenetics and plasmonic nanoparticles activation experiments. In a second stage we will use the network and control theory models to reengineer Hydra’s nervous system, cutting critical connections with laser ablation, transfecting into key neuronal nodes neural actuators or silencers driven by light or small molecules. To goal is to re-program the nervous system, either transiently or permanently, to generate a novel behavior by artificially altering the neural code. In future work, we will extend this approach to more sophisticated behaviors, including feeding and somersaulting locomotion, with the goal of generating synthetic complex behaviors. This project would represent the first systematic neural code-breaking to date and could revolutionize neuroscience, artificial intelligence and control systems by discovering novel algorithms of neural-inspired distributed biological control. Our work will also pioneer synthetic neurobiology, enabling the design of novel behaviors. Our project will highly impact four critical areas. 1) Neuroscience: this work will arguably represent the first example of a completely understood neural code, and one that can be used as a theoretical and experimental model for the decoding of neural activity in other organisms. It could lead to the reinterpretation of the concept of neural circuits from a control theory perspective, as a paradigm shift. 2) Control Systems Engineering: We expect to learn principles of biological control that will be scalable and generalizable to other complex systems. 3) Synthetic Biology: This will be the first metazoan experimental platform with a nervous system that can be precisely engineered, which will likely have a transformative effect in this field. 4) Robotics: This knowledge could be leveraged in man-made technology, including complex systems and soft robotics, and train a new interdisciplinary generation of synthetic neurobiologists. The PI, Rafael Yuste (Columbia University) is a neurobiologist, expert in imaging and optogenetics of neural circuits, and whose lab has recently achieved the complete Rafael Yuste, Columbia University imaging of neuronal and muscle activity of Hydra. The two Columbia University postdocs who will carry out the main Aims are experts in Hydra imaging and computational modeling. The collaborator, Jeff Lichtman (Harvard University), is one of the pioneers in the field of connectomics and will carry out with a postdoc the reconstruction of the nervous system of Hydra