Biology subjects

Beets, I.

Publications and source records attributed to Beets, I..

At least 19 recordsLinked to original sources

bioRxiv2026

K2P Channels Regulate Presynaptic Organisation through a Membrane Potential-Independent Mechanism

Neuronal ion channels have well-established effects on synaptic plasticity, in many cases by influencing pathways that depend on membrane excitability. Here we find that a C. elegans two-pore domain potassium (K2P) channel, TWK-40, regulates presynaptic organisation through a membrane potential-independent mechanism. Instead, this mechanism depends on TWK-40's effects on intracellular potassium levels. Loss-of-function mutations in TWK-40 lead to excessive presynaptic protein accumulation, while gain-of-function mutations lead to depleted presynaptic components and cause synaptic transmission deficits. These abnormalities are phenocopied by transporter mutations that mimic TWK-40's effects on intracellular potassium concentration, but not by sodium channel mutations that mimic its effects on membrane excitability. This indicates that cytoplasmic potassium promotes presynaptic assembly. This process depends on the PYK-1 pyruvate kinase, a potassium-sensitive enzyme, and three transcription factors. These findings establish a new pathway linking neuronal potassium homeostasis to the control of presynaptic organisation and synaptic function.

molecular biology↗

bioRxiv2026

Autocrine feedback maintains homeostatic neuropeptide expression in a peptidergichub neuron

Neuronal circuits sustain stable function by self-regulating their gene expression and neurosecretion. Patterns for autocrine feedback by neuropeptides are widespread across nervous systems, but how they contribute to neuronal homeostasis remains poorly understood. Here, we identify an autocrine homeostatic mechanism in a C. elegans peptidergic hub neuron. FLP-1 neuropeptide release activates the inhibitory receptor DMSR-7 on the AVK hub neurons to self-regulate flp-1 transcription, dense-core vesicle accumulation, and peptide secretion. We show that a parallel PDF-1/PDFR-1 pathway drives flp-1 expression, establishing a "push-and-pull" peptidergic feedback on the AVK neurons. AVKs peptidergic output also depends on the number of FLP-1 peptides encoded in its precursor, revealing a dosage mechanism in behavioral regulation. Moreover, flp-1 expression coordinates transcript levels of additional neuropeptides in AVK. These findings uncover FLP-1 as a self-regulating homeostatic controller within a peptidergic hub neuron and illustrate how precursor-encoded redundancy supports stable yet adaptable circuit states.

neuroscience↗

bioRxiv2025

DeorphaNN: Virtual screening of GPCR peptide agonists using AlphaFold-predicted active state complexes and deep learning embeddings

Peptide-activated G protein-coupled receptors (GPCRs) regulate critical physiological processes such as metabolism, neural signalling, and endocrine function through their interaction with neuropeptides and peptide hormones. Despite their importance, identifying endogenous peptide agonists for GPCRs remains challenging, particularly for orphan receptors without known ligands. Recent advances in deep learning-based protein structure prediction, exemplified by AlphaFold (AF), have shown application beyond structural modelling, including protein-protein interaction prediction. Given that GPCR-peptide agonist interactions represent a specialized form of protein-protein interaction, we leveraged a dataset of experimentally validated agonist and non-agonist GPCR-peptide interactions from Caenorhabditis elegans to evaluate AF-Multimers ability to distinguish agonist-bound complexes. When modelling GPCR-peptide complexes, AF-Multimer confidence metrics partially discriminate agonist from non-agonist interactions, with improved discrimination achieved by utilizing AF-Multistate-derived active-state templates. We further investigated whether embeddings from the hidden layer of AF-Multimers neural network could distinguish agonist from non-agonist complexes. Feature performance analysis reveals that AF- Multimers pair representations outperform single representations, with distinct subregions of the pair representation providing complementary predictive signals. Building on these insights, we developed DeorphaNN, a graph neural network integrating active-state GPCR-peptide structural predictions, interatomic interactions, and deep learning embeddings to prioritize GPCR-peptide agonist interactions. DeorphaNN generalizes across datasets derived from different species, including annelids and humans, and successfully uncovered peptide agonists for two orphan GPCRs. DeorphaNN offers a novel computational resource to accelerate deorphanization by prioritizing GPCR-peptide agonist candidates for AI-guided experimental validation.

bioinformatics↗

bioRxiv2024

Molecular patterns of evolutionary changes throughout the whole nervous system of multiple nematode species

One avenue to better understand brain evolution is to map molecular patterns of evolutionary changes in neuronal cell types across entire nervous systems of distantly related species. Generating whole-animal single-cell transcriptomes of three nematode species from the Caenorhabditis genus, we observed a remarkable stability of neuronal cell type identities over more than 45 million years of evolution. Conserved patterns of combinatorial expression of homeodomain transcription factors are among the best classifiers of homologous neuron classes. Unexpectedly, we discover an extensive divergence in neuronal signaling pathways. While identities of neurotransmitter-producing neurons (glutamate, acetylcholine, GABA and several monoamines) remain stable, ionotropic and metabotropic receptors for all these neurotransmitter systems show substantial divergence, resulting in more than half of all neuron classes changing their capacity to be receptive to specific neurotransmitters. Neuropeptidergic signaling is also remarkably divergent, both at the level of neuropeptide expression and receptor expression, yet the overall dense network topology of the wireless neuropeptidergic connectome remains stable. Novel neuronal signaling pathways are suggested by our discovery of small secreted proteins that show no obvious hallmarks of conventional neuropeptides, but show similar patterns of highly neuron-type-specific and highly evolvable expression profiles. In conclusion, by investigating the evolution of entire nervous systems at the resolution of single neuron classes, we uncover patterns that may reflect basic principles governing evolutionary novelty in neuronal circuits.

evolutionary biology↗

bioRxiv2024

Exploitation of phylum-spanning omics resources reveals complexity in the nematode FLP signalling system and provides insights into flp-gene evolution

BackgroundParasitic nematodes significantly undermine global human and animal health and productivity. Parasite control is reliant on anthelmintic administration however over-use of a limited number of drugs has resulted in escalating parasitic nematode resistance, threatening the sustainability of parasite control and underscoring an urgent need for the development of novel therapeutics. FMRFamide-like peptides (FLPs), the largest family of nematode neuropeptides, modulate nematode behaviours including those important for parasite survival, highlighting FLP receptors (FLP-GPCRs) as appealing putative novel anthelmintic targets. Advances in omics resources have enabled the identification of FLPs and neuropeptide-GPCRs in some parasitic nematodes, but remaining gaps in FLP-ligand libraries hinder the characterisation of receptor-ligand interactions, which are required to drive the development of novel control approaches. ResultsIn this study we exploited recent expansions in nematode genome data to identify 2143 flp-genes in >100 nematode species across free-living, entomopathogenic, plant, animal and human lifestyles and representing 7 of the 12 major nematode clades (1). Our data reveal that: (i) the phylum-spanning flps, flp-1, -8, -14, and -18, may be representative of the flp profile of the last common ancestor of nematodes; (ii) the majority of parasitic nematodes have a reduced flp complement relative to free-living species; (iii) FLP prepropeptide architecture is variable within and between flp-genes and across nematode species; (iv) FLP prepropeptide signatures facilitate flp-gene discrimination; (v) FLP motifs display variable length, amino acid sequence, and conservation; (vi) CLANS analysis provides insight into the evolutionary history of flp-gene sequelogues and reveals putative flp-gene paralogues and, (viii) flp expression is upregulated in the infective larval stage of several nematode parasites. ConclusionsThese data provide the foundation required for phylum-spanning FLP-GPCR deorphanisation screens in nematodes to seed the discovery and development of novel parasite control approaches.

evolutionary biology↗

bioRxiv2024

Cell non-autonomous signaling through the conserved C. elegans glycopeptide hormone receptor FSHR-1 regulates cholinergic neurotransmission

Modulation of neurotransmission is key for organismal responses to varying physiological contexts such as during infection, injury, or other stresses, as well as in learning and memory and for sensory adaptation. Roles for cell autonomous neuromodulatory mechanisms in these processes have been well described. The importance of cell non-autonomous pathways for inter-tissue signaling, such as gut-to-brain or glia-to-neuron, has emerged more recently, but the cellular mechanisms mediating such regulation remain comparatively unexplored. Glycoproteins and their G protein-coupled receptors (GPCRs) are well-established orchestrators of multi-tissue signaling events that govern diverse physiological processes through both cell-autonomous and cell non-autonomous regulation. Here, we show that follicle stimulating hormone receptor, FSHR-1, the sole Caenorhabditis elegans ortholog of mammalian glycoprotein hormone GPCRs, is important for cell non-autonomous modulation of synaptic transmission. Inhibition of fshr-1 expression reduces muscle contraction and leads to synaptic vesicle accumulation in cholinergic motor neurons. The neuromuscular and locomotor defects in fshr-1 loss-of-function mutants are associated with an underlying accumulation of synaptic vesicles, build-up of the synaptic vesicle priming factor UNC-10/RIM, and decreased synaptic vesicle release from cholinergic motor neurons. Restoration of FSHR-1 to the intestine is sufficient to restore neuromuscular activity and synaptic vesicle localization to fshr-1-deficient animals. Intestine-specific knockdown of FSHR-1 reduces neuromuscular function, indicating FSHR-1 is both necessary and sufficient in the intestine for its neuromuscular effects. Re-expression of FSHR-1 in other sites of endogenous expression, including glial cells and neurons, also restored some neuromuscular deficits, indicating potential cross-tissue regulation from these tissues as well. Genetic interaction studies provide evidence that downstream effectors gsa-1/GS, acy-1/adenylyl cyclase and sphk-1/sphingosine kinase and glycoprotein hormone subunit orthologs, GPLA-1/GPA2 and GPLB-1/GPB5, are important for FSHR-1 modulation of the NMJ. Together, our results demonstrate that FSHR-1 modulation directs inter-tissue signaling systems, which promote synaptic vesicle release at neuromuscular synapses.

neuroscience↗

bioRxiv2023

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

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 light eTOC 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.

neuroscience↗

bioRxiv2023

An ancient thyrostimulin-like neuroendocrine pathway regulates growth in Caenorhabditis elegans

In vertebrates, thyrostimulin is a highly conserved glycoprotein hormone that, besides thyroid stimulating hormone (TSH), is a potent ligand of the TSH receptor. Thyrostimulin is considered the most ancestral glycoprotein hormone and orthologs of its subunits, GPA2 and GPB5, are widely conserved across vertebrate and invertebrate animals. Unlike TSH, however, the functions of the thyrostimulin neuroendocrine system remain largely unexplored. Here, we identify a functional thyrostimulin-like signaling system in Caenorhabditis elegans. We show that orthologs of GPA2 and GPB5, together with thyrotropin-releasing hormone (TRH) related neuropeptides, constitute a neuroendocrine pathway that promotes growth in C. elegans. GPA2/GPB5 signaling is required for normal body size and acts through activation of the glycoprotein hormone receptor ortholog FSHR-1. C. elegans GPA2 and GPB5 increase cAMP signaling by FSHR-1 in vitro. Both subunits are expressed in enteric neurons and promote growth by signaling to their receptor in glial cells and the intestine. Impaired GPA2/GPB5 signaling causes bloating of the intestinal lumen. In addition, mutants lacking thyrostimulin-like signaling are defective in defecation behavior. Our study suggests that the thyrostimulin GPA2/GPB5 pathway is an ancient enteric neuroendocrine system that regulates intestinal function in ecdysozoans, and may ancestrally have been involved in the control of organismal growth.

neuroscience↗

bioRxiv2022

System-wide mapping of neuropeptide-GPCR interactions in C. elegans

Neuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map in C. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network. HighlightsO_LISystem-wide reverse pharmacology deorphanizes 68 C. elegans peptide GPCRs C_LIO_LIDiscovery of 461 peptide-GPCR pairs and additional ligands for characterized GPCRs C_LIO_LINeuropeptides show specific and complex combinatorial receptor interactions C_LIO_LIPeptide-GPCR pairs support long-range conservation and expansion of peptide systems C_LI

neuroscience↗

bioRxiv2022

The neuropeptidergic connectome of C. elegans

SummaryEfforts are currently ongoing to map synaptic wiring diagrams or connectomes in order to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene expression datasets with a biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This connectome is characterized by a high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several of the most important nodes in this connectome are little-studied neurons that are specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand basic organizational principles of neuroendocrine signaling networks.

neuroscience↗

bioRxiv2022

Molecular characteristics of diel rhythmic diversity reveal disconnection between different levels of organismal rhythmicity

The circadian clock controls behavior and metabolism in various organisms. However, the exact timing and strength of rhythmic phenotypes can vary significantly between individuals of the same species. This is highly relevant for the rhythmically complex marine environments where organismal rhythmic diversity likely permits the occupation of different microenvironments. When investigating circadian locomotor behavior of Platynereis dumerilii, a model system for marine molecular chronobiology, we found strain-specific, high variability between individual worms. The individual patterns were reproducibly maintained for several weeks independent of basic culture conditions, such as population density or feeding. A diel head transcriptome comparison of behaviorally rhythmic versus arrhythmic wildtype worms showed that 24h cycling of core circadian clock transcripts is identical between both behavioral phenotypes. While behaviorally arrhythmic worms showed a similar total number of cycling transcripts compared to their behaviorally rhythmic counterparts, the annotation categories of their transcripts, however, differed substantially. Consistent with their locomotor phenotype, behaviorally rhythmic worms exhibit an enrichment of cycling transcripts related to neuronal/behavioral processes. In contrast, behaviorally arrhythmic worms showed significantly increased diel cycling for metabolism- and physiology-related transcripts. Phenotype-specific cycling of distinct matrix metalloproteinase transcripts, encoding extracellular enzymes that modulate synaptic circuit function and neuropeptide signaling, like pigment dispersing factor (PDF), prompted us to functionally investigate Platynereis pdf. Differing from its role in Drosophila, loss of pdf impacts on overall activity levels, but shows only indirect effects on rhythmicity. Our results show that individuals arrhythmic in a given process can show increased rhythmicity in others. Across the Platynereis population, variations of this exist as a reproducible continuum. We hypothesize that such diel rhythm breadth is an important biodiversity resource enabling the species to quickly adapt to heterogeneous marine environments and potentially also to the effects of climate change, which is however endangered with shrinking population sizes and hence diversity.

animal behavior and cognition↗

bioRxiv2022

Multisite gating in tonic sensory circuits integrates multimodal context to control persistent behavioral states

Maintaining or shifting between behavioral states according to context is essential for animals to implement fitness-promoting strategies. How integration of internal state, past experience and sensory inputs orchestrate persistent multidimensional behavior changes remains poorly understood. Here, we show that C. elegans integrates food availability and environment temperature over different timescales to engage in persistent dwelling, scanning, global or glocal search strategies matching thermoregulatory and feeding needs. Transition between states, in each case, requires lifting multiple regulatory gates including AFD or FLP tonic sensory neurons activity, neuropeptide expression and downstream circuit responsiveness. State-specific FLP-6 or FLP-5 neuropeptide signaling acts on a distributed set of inhibitory receptors to promote scanning or glocal search, respectively, bypassing dopamine and glutamate-dependent behavioral state control. Multisite gating-dependent behavioral switch by GPCRs in tonic sensory circuits might represent a conserved regulatory logic for persistent behavioral state transitions enabling a flexible prioritization on the valance of multiple inputs.

neuroscience↗

bioRxiv2022

Peptidergic signaling controls the dynamics of sickness behavior in Caenorhabditis elegans

Pathogenic infection elicits sickness behaviors that promote recovery and survival of the host. For example, following infection with the pathogenic bacterium Pseudomonas aeruginosa PA14, the nematode Caenorhabditis elegans modifies its sensory preferences to avoid the pathogen. Here we identify antagonistic neuromodulatory circuits that shape this sickness behavior. Using an unbiased cell-directed neuropeptide screen, we show that AVK neurons upregulate and release FMRFamide-like FLP-1 neuropeptides during infection to drive pathogen avoidance. Manipulations that increase or decrease AVK signaling accelerate or delay pathogen avoidance, respectively, implicating AVK in the dynamics of sickness behavior. FLP-1 neuropeptides act via the G-protein-coupled receptor DMSR-7 in RIM/RIC neurons to reduce tyraminergic/octopaminergic signaling that opposes pathogen avoidance. RIM/RIC neurons relay parallel signals from neuropeptides and the cytokine TGF-{beta} that represent internal and external regulators of pathogen avoidance. Our results demonstrate that antagonism between neuromodulatory systems results in slow, graded transitions between alternative behavioral states.

neuroscience↗

bioRxiv2021

Neuropeptide signalling shapes feeding and reproductive behaviours in male C. elegans

Sexual dimorphism occurs where different sexes of the same species display differences in characteristics not limited to reproduction. For the nematode Caenorhabditis elegans, in which the complete neuroanatomy has been solved for both hermaphrodites and males, sexually dimorphic features have been observed both in terms of the number of neurons and in synaptic connectivity. In addition, male behaviours, such as food-leaving to prioritise searching for mates, have been attributed to neuropeptides released from sex-shared or sex-specific neurons. In this study, we show that the lury-1 neuropeptide gene shows a sexually dimorphic expression pattern; being expressed in pharyngeal neurons in both sexes but displaying additional expression in tail neurons only in the male. We also show that lury-1 mutant animals show sex differences in feeding behaviours, with pharyngeal pumping elevated in hermaphrodites but reduced in males. LURY-1 also modulates male mating efficiency, influencing motor events during contact with a hermaphrodite. Our findings indicate sex-specific roles of this peptide in feeding and reproduction in C. elegans, providing further insight into neuromodulatory control of sexually dimorphic behaviours.

neuroscience↗

bioRxiv2021

The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

A key question in current immunology is how the innate immune system generates high levels of specificity. Using the Caenorhabditis elegans model system, we demonstrate that functional loss of NMUR-1, a neuronal G protein-coupled receptor homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans innate immunity against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors involved in binding to RNA polymerase II regulatory regions, which, in turn, controls the expression of distinct immune genes in response to different pathogens. These results uncovered a molecular basis for the specificity of C. elegans innate immunity. Given the evolutionary conservation of NMUR-1 signaling in immune regulation across multicellular organisms, our study could provide mechanistic insights into understanding the specificity of innate immunity in other animals, including mammals.

microbiology↗

bioRxiv2020

Distinct Neuropeptide-Receptor Modules Regulate a Sex-Specific Behavioral Response to a Pheromone

Dioecious species are a hallmark of the animal kingdom, with opposing sexes responding differently to identical sensory cues. Here, we study the response of C. elegans to the small-molecule pheromone, ascr#8, which elicits opposing behavioral valences in each sex. We identify a novel neuropeptide-neuropeptide receptor (NP/NPR) module that is active in males, but not in hermaphrodites. Using a novel paradigm of neuropeptide rescue that we established, we leverage bacterial expression of individual peptides to rescue the sex-specific response to ascr#8. Concurrent biochemical studies confirmed individual FLP-3 peptides differentially activate two divergent receptors, NPR-10 and FRPR-16. Interestingly, the two of the peptides that rescued behavior in our feeding paradigm are related through a conserved threonine, suggesting that a specific NP/NPR combination sets a male state, driving the correct behavioral valence of the ascr#8 response. Receptor expression within pre-motor neurons reveals novel coordination of male-specific and core locomotory circuitries.

neuroscience↗

bioRxiv2020

Extrasynaptic volume transmission: A novel route for neuropeptide signaling in nematodes

Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other non-synaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of Caenorhabditis elegans neurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematode Ascaris suum FMRFamide-like peptides encoded on flp-18 potently stimulate female reproductive organs but are only expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we report a new non-synaptic mode of signaling in nematodes mediated by neuropeptides within the PCF. Our data show that: (i) A. suum PCF (As-PCF) contains a catalogue of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins; (ii) the A. suum FMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome; (iii) As-PCF potently modulates nematode reproductive muscle function ex vivo, mirroring the effects of synthetic FLP-18 peptides; (iv) As-PCF activates the C. elegans FLP-18 receptors NPR-4 and -5; (v) As-PCF alters C. elegans behavior and, (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. Here we provide the first direct experimental evidence that supports an extrasynaptic volume route for neuropeptide transmission in nematodes. These data demonstrate non-synaptic signaling within the nematode functional connectome and are pertinent to receptor deorphanisation approaches underpinning drug discovery programs for nematode pathogens.

neuroscience↗

bioRxiv2020

A conserved neuropeptide system links head and body motor circuits to enable adaptive behavior

Neuromodulators promote adaptive behaviors that are often complex and involve concerted activity changes across circuits that are often not physically connected. It is not well understood how neuromodulatory systems accomplish these tasks. Here we show that the C. elegans NLP-12 neuropeptide system shapes responses to food availability by modulating the activity of head and body wall motor neurons through alternate G-protein coupled receptor (GPCR) targets, CKR-1 and CKR-2. We show ckr-2 deletion reduces body bend depth during movement under basal conditions. We demonstrate CKR-1 is a functional NLP-12 receptor and define its expression in the nervous system. In contrast to basal locomotion, biased CKR-1 GPCR stimulation of head motor neurons promotes turning during local searching. Deletion of ckr-1 reduces head neuron activity and diminishes turning while specific ckr-1 overexpression or head neuron activation promote turning. Thus, our studies suggest locomotor responses to changing food availability are regulated through conditional NLP-12 stimulation of head or body wall motor circuits. Impact statementInvestigation of neuromodulatory control of ethologically conserved area-restricted food search behavior shows that NLP-12 stimulation of the head motor circuit promotes food searching through the previously uncharacterized CKR-1 GPCR.

neuroscience↗