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Published August 8, 2022 | public
Journal Article Open

Brain-wide bidirectional neuropeptide modulation of individual neuron classes regulates a developmental decision


Secreted neuromodulators, like biogenic amines and neuropeptides, can reconfigure circuit functions both locally and at a distance and establish global brain states that alter circuit outputs over prolonged timescales. Despite their diversity and ubiquitous presence, many studies on neuromodulation tend to focus on dissecting the function and site of action of individual neuropeptides. Here, we take a different approach by conducting a systems-level investigation of neuropeptide receptor signaling function and cell-type-specific distribution in the context of the Caenorhabditis elegans diapause entry developmental decision. C. elegans diapause entry is controlled by sensory perception of external factors and is regulated by neuropeptide signaling. We performed a comprehensive functional screen of neuropeptide receptor mutants for pheromone-induced diapause entry phenotypes and integrated these results with published C. elegans single-cell RNA-seq data to reveal that almost all neuron classes expressed at least one receptor with a role in diapause entry. Our receptor expression analysis also identified four highly modulated neural hubs with no previously reported roles in diapause entry that are distributed throughout the animal's body, possibly as a means of synchronizing the whole-organism transition into the appropriate larval morph. Furthermore, most neuron classes expressed unique neuropeptide receptor repertoires that have opposing effects on the diapause entry decision. We propose that brain-wide antagonistic neuropeptide modulation of individual neuron classes by distinct neuropeptide receptor subsets could serve as a strategy against overmodulation and that this motif might generalize to other decision-making paradigms in other organisms.

Additional Information

© 2022 Elsevier. Received 12 January 2022, Revised 6 May 2022, Accepted 17 May 2022, Available online 8 June 2022. We thank Wilber Palma for sharing the flp-8 and pks-1 promoter fragments. We also thank Barbara J. Perry for assistance with strain freezing and Dr. Tsui-Fen Chou for providing Cas9 protein. Figures 1A, 4A, and 4C were created with BioRender.com. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Some strains were provided by the lab of Dr. Shohei Mitani as part of the National Bioresource Project. P.W.S., C.M.C., and H.P. were funded by NIH grants R24OD023041 and UF1NS111697. Author contributions. Conceptualization and methodology, C.M.C.; crude pheromone extraction, dauer formation assays, molecular cloning, transgenesis, microscopy, data analysis, and visualization, C.M.C.; CRISPR mutagenesis, H.P.; funding acquisition, P.W.S.; paper writing, C.M.C. Data and code availability. All data reported in this paper will be shared by the lead contact upon request. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. This study did not generate any unique code. The authors declare no competing interests.

Attached Files

Supplemental Material - 1-s2.0-S096098222200851X-mmc1.pdf

Supplemental Material - 1-s2.0-S096098222200851X-mmc2.xlsx

Supplemental Material - 1-s2.0-S096098222200851X-mmc3.xlsx

Supplemental Material - 1-s2.0-S096098222200851X-mmc4.xlsx

Supplemental Material - 1-s2.0-S096098222200851X-mmc5.xlsx

Supplemental Material - 1-s2.0-S096098222200851X-mmc6.xlsx


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Additional details

August 22, 2023
August 22, 2023