RT Journal Article SR Electronic T1 Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.11.23.568473 DO 10.1101/2023.11.23.568473 A1 Aoki, Ichiro A1 Golinelli, Luca A1 Dunkel, Eva A1 Bhat, Shripriya A1 Bassam, Erschad A1 Beets, Isabel A1 Gottschalk, Alexander YR 2023 UL http://biorxiv.org/content/early/2023/11/23/2023.11.23.568473.abstract AB Neuronal communication involves small-molecule transmitters, gap junctions, and neuropeptides. While neurons often express multiple neuropeptides, our understanding of the coordination of their action and their mutual interactions remains limited. Here, we demonstrate that two neuropeptides, NLP-10 and FLP-1, released from the same interneuron pair, AVKL/R, exert antagonistic effects on locomotion speed in Caenorhabditis elegans. NLP-10 accelerates locomotion by activating the G protein-coupled receptor NPR- 35 on premotor interneurons that promote forward movement. Notably, we establish that NLP-10 is crucial for the aversive response to mechanical and noxious light stimuli. Conversely, AVK-derived FLP-1 slows down locomotion by suppressing the secretion of NLP-10 from AVK, through autocrine feedback via activation of its receptor DMSR-7 in AVK neurons. Our findings suggest that peptidergic autocrine motifs, exemplified by the interaction between NLP-10 and FLP-1, might represent a widespread mechanism in nervous systems across species. These mutual functional interactions among peptidergic co-transmitters could fine-tune brain activity.Highlights • A pair of neurons elicits opposing behaviors via two distinct neuropeptides• The neuropeptide NLP-10 accelerates locomotion by activating premotor interneurons• Release of the neuropeptide FLP-1 reduces NLP-10 release via autocrine feedback• NLP-10 is crucial for escaping aversive mechanical stimuli and noxious blue lighteTOC blurb Neuropeptidergic communication is complex due to the hundreds of proteinaceous transmitters and receptors involved. Aoki and colleagues demonstrate a further layer of regulation, where one neuropeptide negatively influences release of an antagonistic neuropeptide by autocrine feedback, in a single neuron pair. This may represent a general principle in neuropeptidergic signaling.Competing Interest StatementThe authors have declared no competing interest.