Natural isolates of C. elegans exhibit either solitary or social feeding behavior. Solitary foragers move slowly on a bacterial lawn and disperse across it, while social foragers move rapidly on bacteria and aggregate together. A loss-of-function mutation in the npr-1 gene, which encodes a predicted G protein-coupled receptor similar to neuropeptide Y receptors, causes a solitary strain to take on social behavior. Two isoforms of NPR-1 that differ at a single residue occur in the wild. One isoform, NPR-1 215F, is found exclusively in social strains, while the other isoform, NPR-1 215V, is found exclusively in solitary strains. An NPR-1 215V transgene can induce solitary feeding behavior in a wild social strain. Thus, isoforms of a putative neuropeptide receptor generate natural variation in C. elegans feeding behavior.

A current challenge in neuroscience is to bridge the gaps between genes, proteins, neurons, neural circuits, and behavior in a single animal model. The nematode Caenorhabditis elegans has unique features that facilitate this synthesis. Its nervous system includes exactly 302 neurons, and their pattern of synaptic connectivity is known. With only five olfactory neurons, C. elegans can dynamically respond to dozens of attractive and repellent odors. Thermosensory neurons enable the nematode to remember its cultivation temperature and to track narrow isotherms. Polymodal sensory neurons detect a wide range of nociceptive cues and signal robust escape responses. Pairing of sensory stimuli leads to long-lived changes in behavior consistent with associative learning. Worms exhibit social behaviors and complex ultradian rhythms driven by Ca(2+) oscillators with clock-like properties. Genetic analysis has identified gene products required for nervous system function and elucidated the molecular and neural bases of behaviors.

Social and solitary feeding in natural Caenorhabditis elegans isolates are associated with two alleles of the orphan G-protein-coupled receptor (GPCR) NPR-1: social feeders contain NPR-1 215F, whereas solitary feeders contain NPR-1 215V. Here we identify FMRFamide-related neuropeptides (FaRPs) encoded by the flp-18 and flp-21 genes as NPR-1 ligands and show that these peptides can differentially activate the NPR-1 215F and NPR-1 215V receptors. Multicopy overexpression of flp-21 transformed wild social animals into solitary feeders. Conversely, a flp-21 deletion partially phenocopied the npr-1(null) phenotype, which is consistent with NPR-1 activation by FLP-21 in vivo but also implicates other ligands for NPR-1. Phylogenetic studies indicate that the dominant npr-1 215V allele likely arose from an ancestral npr-1 215F gene in C. elegans. Our data suggest a model in which solitary feeding evolved in an ancestral social strain of C. elegans by a gain-of-function mutation that modified the response of NPR-1 to FLP-18 and FLP-21 ligands.

To navigate O2 gradients, C. elegans can modulate turning rates and speed of movement. Aerotaxis can be reprogrammed by experience or engineered artificially. We propose a model in which prolonged activation of the AQR, PQR, and URX neurons by low O2 switches on previously inactive O2 sensors. This enables aerotaxis to low O2 environments and may encode a "memory" of previous cultivation in low O2.

Natural Caenorhabditis elegans isolates exhibit either social or solitary feeding on bacteria. We show here that social feeding is induced by nociceptive neurons that detect adverse or stressful conditions. Ablation of the nociceptive neurons ASH and ADL transforms social animals into solitary feeders. Social feeding is probably due to the sensation of noxious chemicals by ASH and ADL neurons; it requires the genes ocr-2 and osm-9, which encode TRP-related transduction channels, and odr-4 and odr-8, which are required to localize sensory chemoreceptors to cilia. Other sensory neurons may suppress social feeding, as social feeding in ocr-2 and odr-4 mutants is restored by mutations in osm-3, a gene required for the development of 26 ciliated sensory neurons. Our data suggest a model for regulation of social feeding by opposing sensory inputs: aversive inputs to nociceptive neurons promote social feeding, whereas antagonistic inputs from neurons that express osm-3 inhibit aggregation.

Homeostasis of internal carbon dioxide (CO2) and oxygen (O2) levels is fundamental to all animals. Here we examine the CO 2 response of the nematode Caenorhabditis elegans. This species inhabits rotting material, which typically has a broad CO 2 concentration range. We show that well fed C. elegans avoid CO 2 levels above 0.5%. Animals can respond to both absolute CO 2 concentrations and changes in CO 2 levels within seconds. Responses to CO 2 do not reflect avoidance of acid pH but appear to define a new sensory response. Sensation of CO 2 is promoted by the cGMPgated ion channel subunits TAX-2 and TAX-4, but other pathways are also important. Robust CO 2 avoidance in well fed animals requires inhibition of the DAF-16 forkhead transcription factor by the insulin-like receptor DAF-2. Starvation, which activates DAF-16, strongly suppresses CO 2 avoidance. Exposure to hypoxia (<1% O2) also suppresses CO 2 avoidance via activation of the hypoxiainducible transcription factor HIF-1. The npr-1 215V allele of the naturally polymorphic neuropeptide receptor npr-1, besides inhibiting avoidance of high ambient O 2 in feeding C. elegans, also promotes avoidance of high CO 2. C. elegans integrates competing O 2 and CO2 sensory inputs so that one response dominates. Food and allelic variation at NPR-1 regulate which response prevails. Our results suggest that multiple sensory inputs are coordinated by C. elegans to generate different coherent foraging strategies.carbon dioxide sensing ͉ natural variation ͉ oxygen sensing C O 2 is an important sensory cue for many organisms. Insects can use elevated CO 2 as part of an alarm signal or to find food (1-3). In fungi, high CO 2 can induce filamentation (4) and regulate sporulation (5). Nematode parasites of plants and animals can follow CO 2 gradients to locate their hosts (6, 7). Internal CO 2 levels also provide important signals. For example, insects and mammals monitor internal CO 2 to modulate respiratory exchange (8-10). This homeostatic function prevents respiratory poisoning and pH changes in body fluids, which can occur if CO 2 levels rise above 5% (11).Several mechanisms have been implicated in sensing CO 2 . In Drosophila, avoidance of high CO 2 is mediated by a pair of odorant receptors (2, 12, 13). Artificially activating neurons expressing these receptors elicits the escape response (14). Less is known about how insects monitor internal CO 2 to control opening of spiracles (15). In mammals internal CO 2 levels regulate breathing, diuresis, blood pH, and blood flow (8). In most cases the molecular sensors involved are unclear although pH changes associated with hydration of CO 2 are thought to be important. Carbonic anhydrases, which catalyze the hydration of CO 2 to produce H ϩ and HCO 3 Ϫ , are widely expressed in mammals. HCO 3 Ϫ has been shown to regulate the activity of a family of adenylate cyclases that is conserved from bacteria to man (16). However, the role of these enzymes in CO 2 signaling in animals is unclear. In fungi an HCO 3 Ϫ -regulated adenylate cy...

Tonic receptors convey stimulus duration and intensity and are implicated in homeostatic control. However, how tonic homeostatic signals are generated, and how they reconfigure neural circuits and modify animal behavior is poorly understood. Here we show that C. elegans O2-sensing neurons are tonic receptors that continuously signal ambient [O2] to set the animal’s behavioral state. Sustained signalling relies on a Ca2+ relay involving L-type voltage-gated Ca2+ channels, the ryanodine and the IP3 receptors. Tonic activity evokes continuous neuropeptide release, which helps elicit the enduring behavioral state associated with high [O2]. Sustained O2 receptor signalling is propagated to downstream neural circuits, including the hub interneuron RMG. O2 receptors evoke similar locomotory states at particular [O2], regardless of previous d[O2]/dt. However, a phasic component of the URX receptors’ response to high d[O2]/dt, as well as tonic-to-phasic transformations in downstream interneurons, enable transient reorientation movements shaped by d[O2]/dt. Our results highlight how tonic homeostatic signals can generate both transient and enduring behavioral change.

Behaviours evolve by iterations of natural selection, but we have few insights into the molecular and neural mechanisms involved. Here we show that some Caenorhabditis elegans wild strains switch between two foraging behaviours in response to subtle changes in ambient oxygen. This finely tuned switch is conferred by a naturally variable hexacoordinated globin, GLB-5. GLB-5 acts with the atypical soluble guanylate cyclases, which are a different type of oxygen binding protein, to tune the dynamic range of oxygen-sensing neurons close to atmospheric (21%) concentrations. Calcium imaging indicates that one group of these neurons is activated when oxygen rises towards 21%, and is inhibited as oxygen drops below 21%. The soluble guanylate cyclase GCY-35 is required for high oxygen to activate the neurons; GLB-5 provides inhibitory input when oxygen decreases below 21%. Together, these oxygen binding proteins tune neuronal and behavioural responses to a narrow oxygen concentration range close to atmospheric levels. The effect of the glb-5 gene on oxygen sensing and foraging is modified by the naturally variable neuropeptide receptor npr-1 (refs 4, 5), providing insights into how polygenic variation reshapes neural circuit function.