Brain-wide bidirectional neuropeptide modulation of individual neuron classes regulates a developmental decision

Secreted neuromodulators, like biogenic amines and neuropeptides, can reconfigure circuit functions both locally and at a distance and establish global brain states that alter circuit outputs over prolonged timescales.^1-3 Despite their diversity and ubiquitous presence, many studies on neuromodulation tend to focus on dissecting the function and site of action of individual neuropeptides. Here, we take a different approach by conducting a systems-level investigation of neuropeptide receptor signaling function and cell-type-specific distribution in the context of the Caenorhabditis elegans diapause entry developmental decision. C. elegans diapause entry is controlled by sensory perception of external factors and is regulated by neuropeptide signaling.^4-8 We performed a comprehensive functional screen of neuropeptide receptor mutants for pheromone-induced diapause entry phenotypes and integrated these results with published C. elegans single-cell RNA-seq data to reveal that almost all neuron classes expressed at least one receptor with a role in diapause entry.⁹ Our receptor expression analysis also identified four highly modulated neural hubs with no previously reported roles in diapause entry that are distributed throughout the animal's body, possibly as a means of synchronizing the whole-organism transition into the appropriate larval morph. Furthermore, most neuron classes expressed unique neuropeptide receptor repertoires that have opposing effects on the diapause entry decision. We propose that brain-wide antagonistic neuropeptide modulation of individual neuron classes by distinct neuropeptide receptor subsets could serve as a strategy against overmodulation and that this motif might generalize to other decision-making paradigms in other organisms.