Decoding Neuropeptide Complexity: Advancing Neurobiological Insights from Invertebrates to Vertebrates through...

Neuropeptides are vital signaling molecules involved in neural communication, hormonal regulation, and stress response across diverse taxa. Despite their critical roles, neuropeptide research remains challenging due to their low abundance, complex post-translational modifications (PTMs), and dynamic expression patterns. Mass spectrometry (MS)-based neuropeptidomics has revolutionized peptide identification and quantification, enabling the high-throughput characterization of neuropeptides and their PTMs. However, the complexity of vertebrate neural networks poses significant challenges for functional studies. Invertebrate models, such as Cancer borealis, Drosophila melanogaster, and Caenorhabditis elegans, offer simplified neural circuits, well-characterized systems, and experimental tools for elucidating the functional roles of neuropeptides. These models have revealed conserved neuropeptide families, including allatostatins, RFamides, and tachykinin-related peptides, whose vertebrate homologues regulate analogous physiological functions. Recent advancements in MS techniques, including ion mobility spectrometry and MALDI MS imaging, have further enhanced the spatial and temporal resolution of neuropeptide analysis, allowing for insights into peptide signaling systems. Invertebrate neuropeptide research not only expands our understanding of conserved neuropeptide functions but also informs translational applications including the development of peptide-based therapeutics. This review highlights the utility of invertebrate models in neuropeptide discovery, emphasizing their contributions to uncovering fundamental biological principles and their relevance to vertebrate systems.