A brain-gut excitatory peptide/CCHamide homolog regulates satiation and motivational state transitions in the Aplysia feeding circuit

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Excitatory peptide (EP) and CCHamide (CCHa) are protostome neuropeptides originally identified in lophotrochozoans (including annelids and mollusks) and arthropods, respectively, and are homologous to the deuterostome endothelin (ET) and gastrin-releasing peptide (GRP)/neuromedin-B (NMB) systems. These peptides are brain-gut peptides: in vertebrates, GRP/NMB function as satiety peptides, whereas arthropod CCHa displays species-specific actions, either inhibiting or promoting feeding. However, the mechanisms by which these peptides modulate feeding circuits remain unknown. Here, we investigated the EP/CCHa signaling pathway in Aplysia, a mollusk with a well-defined feeding circuit. We identified a single precursor encoding Aplysia EP/CCHa (apEP/CCHa). Mass spectrometry demonstrated that an apEP/CCHa peptide is present in the central ganglia. In situ hybridization and immunohistochemistry revealed apEP/CCHa-positive neurons in the CNS, immunopositive cells in the gut, and immunopositive fibers in the gut-innervating esophageal nerve. To identify potential targets, we cloned two novel apEP/CCHa receptors. Phylogenetically, one receptor clusters with lophotrochozoan EP/CCHa receptors, whereas the other unexpectedly clusters with arthropod receptors, suggesting independent lineages for the two receptors. Single-cell RNA sequencing showed that both receptors are expressed in the key feeding central pattern generator (CPG) interneurons B20 and B34. Functionally, apEP/CCHa inhibited food intake in vivo and converted ingestive motor programs to egestive ones in vitro. At the circuit level, apEP/CCHa modulated excitability of B20 and B34, and two additional interneurons (B40, B64). In summary, we demonstrate that apEP/CCHa is a brain-gut peptide that functions as a satiation signal, and identify specific feeding CPG elements through which apEP/CCHa regulates motivational state transitions.

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