Dense and distributed neuropeptide network in the nerve net of Hydra vulgaris.

Neuroscience has long emphasized synaptic transmission and physical wiring as the substrate of brain function and behavior. However, an additional layer of connectivity - a "chemical connectome" formed by neuropeptide-GPCR signaling - has been increasingly recognized in animals such as C. elegans, Drosophila, and the cnidarian Nematostella vectensis. To further explore neuropeptide networks in basal metazoans, we analyzed the genome and transcriptome of the freshwater cnidarian Hydra vulgaris. Hydra offers unique experimental advantages: a simple nerve net, robust regenerative capacity, a well described behavioral repertoire, and tractable whole-body calcium imaging that allows mapping of neural and muscle activity, and cell type identity, in an integrated manner. This makes Hydra a powerful system to investigate how neuropeptidergic signaling shapes neuronal ensembles and behavior. Here, we identify 61 putative unique neuropeptides and 65 neuropeptide-specific G protein-coupled receptors (GPCRs). We show that different neuronal cell types display specific neuropeptide and receptor expression profiles, suggestive of defined communication pathways within Hydra´s decentralized nervous system. Network topology analysis of the neuropeptide network reveals a dense and distributed signaling architecture, with ectodermal neurons acting as centralized hubs for organism-wide coordination. Computational simulations using a simplified model of the nerve net demonstrate that this architecture can implement stable dynamical states. Our study reveals a comprehensive neuropeptidergic network in a non-bilaterian species, highlighting the evolutionary continuity and functional relevance of wireless chemical networks for complex behavior. Moreover, the distributed and recurrent connectivity we uncover suggests the existence in nervous systems of attractor neural networks implemented with chemical signaling, as opposed to synaptic wiring.