Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair

Abstract

SummaryNeuronal 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 inCaenorhabditis 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 blurbNeuropeptidergic 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.

Antagonism between neuropeptides and monoamines in a distributed circuit for pathogen avoidance

“…A feedback function of flp-1/dmsr-7 on AVK can also affect locomotion in the absence of pathogen. 40 We did not observe rescue when dmsr-7 was expressed in a set of neurons including RIM but not RIC ( glr-1+ ) or in ventral cord motor neurons ( acr-2+ ) ( Figures 4 K, 4L, S4 G, and S4H).…”

“… 56 At the same time, AVK is not solely a pathogen-detecting neuron because AVK and its component neuropeptides have locomotor functions in the absence of pathogens. 31 , 40 , 57 Instead, the aggregate results support a distributed and combinatorial logic for the action of FLP-1 neuropeptides in multiple behaviors.…”

“…Moreover, neuropeptide release itself can be regulated with remarkable specificity: in locomotion, AVK-derived FLP-1 inhibits AVK release of an antagonistic neuropeptide, NLP-10. 40 This result further highlights the combinatorial nature of neuromodulation. We attempted to preserve the natural regulatory context of egl-3 , flp-1 , and dmsr-7 by expressing them in subsets of their normal expression patterns, but in some cases, even these experiments may have generated unnatural combinations of neuromodulatory signals.…”

Evolutionary conserved peptide and glycoprotein hormone-like neuroendocrine systems in C. elegans

“…While SIFP-1 is the cognate ligand of the NPFF/SIFamide receptor SIFR-1/NPR-35 in vitro ( Beets et al, 2023 ), its involvement in mediating the effects of SIFP-1 on pharyngeal pumping has not been explored yet. Conversely, SIFP-1/SIFR-1 signaling as a ligand/receptor pair has recently been demonstrated in the regulation of locomotor responses to aversive mechanical and light stimulation, and AVK-driven acceleration in locomotion ( Aoki et al, 2023 ). In these responses, SIFR-1 is required in AVB and/or AIY (premotor interneurons) ( Aoki et al, 2023 ).…”

“…Conversely, SIFP-1/SIFR-1 signaling as a ligand/receptor pair has recently been demonstrated in the regulation of locomotor responses to aversive mechanical and light stimulation, and AVK-driven acceleration in locomotion ( Aoki et al, 2023 ). In these responses, SIFR-1 is required in AVB and/or AIY (premotor interneurons) ( Aoki et al, 2023 ).…”