Mapping and decoding neuropeptide signaling networks in nervous system function

Neuropeptides are widespread signaling molecules that are central to brain function in all animals. Recent advances in profiling their expression across neural circuits, in conjunction with detailed biochemical characterization of their interactions with receptors, have made it feasible to build brain-wide maps of neuropeptide signaling. Here, we discuss how recent reconstructions of neuropeptide signaling networks, from mammalian brain regions to nervous system-wide maps in C. elegans, reveal conserved organizational features of neuropeptidergic networks. Furthermore, we review recent technical breakthroughs in in vivo sensors for peptide release, receptor binding, and intracellular signaling that bring a mechanistic understanding of neuropeptide networks within experimental reach. Finally, we describe how the architecture of neuropeptide signaling networks can change throughout evolution or even the lifetime of individuals, which highlights the complexities that must be considered to understand how these molecules modulate circuit activity and behavior across different contexts.