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

## TL;DR

This study reveals a complex chemical communication network in Hydra, showing that neuropeptides can coordinate behavior without a centralized brain.

## Contribution

The discovery of a dense and distributed neuropeptide network in Hydra vulgaris, suggesting ancient origins of chemical signaling in nervous systems.

## Key findings

- Hydra has 61 putative neuropeptides and 65 neuropeptide-specific GPCRs, forming a rich chemical communication network.
- Ectodermal neurons act as hubs in the neuropeptide network, enabling organism-wide coordination.
- Computational models show the network can support stable activity patterns, similar to attractor neural networks.

## Abstract

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.

For more than a century, neuroscience has focused on connections between neurons via synapses as the main basis of brain function. In this study, we explore an additional and less understood layer of neuronal communication: chemical signaling, mediated by small diffusible molecules called neuropeptides. Neuropeptides are conserved across organisms and also present in humans and do not require synaptic wiring and instead can act more like radio broadcast messages, reaching many cells at once, and activating only those with the right receptor. We chose the simple freshwater animal Hydra to study this form of communication because its nervous system is small, accessible, and can be studied with whole-body imaging and genetic analysis. By analyzing its genome and gene expression, we identified a rich set of neuropeptides and their matching receptors, revealing an extensive chemical communication network. We found that different neuron types use distinct combinations of these signals, suggesting organized communication pathways despite the absence of a centralized brain. By modeling this network, we show that such chemical signaling alone can support stable patterns of activity, similar to the neural networks thought to underlie behavior and memory in more complex brains. Our findings suggest that chemical communication is an ancient and fundamental principle of nervous system organization, providing a complementary framework to synaptic wiring for understanding how brains generate behavior.