RESUMEN
Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR-1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses of unc-1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteostasis , Metabolismo de los Lípidos/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Esteroides/metabolismoRESUMEN
Trimethylglycine, or betaine, is an amino acid derivative found in diverse organisms, from bacteria to plants and animals, with well-established functions as a methyl donor and osmolyte in all cells. In addition, betaine is found in the nervous system, though its function there is not well understood. Here, we show that betaine is synthesized in the nervous system of the nematode worm, Caenorhabditis elegans, where it functions in the control of different behavioral states. Specifically, we find that betaine can be produced in a pair of interneurons, the RIMs, and packed into synaptic vesicles by the vesicular monoamine transporter, CAT-1, expressed in these cells. Mutant animals defective in betaine synthesis are unable to control the switch from local to global foraging, a phenotype that can be rescued by restoring betaine specifically to the RIM neurons. These effects on behavior are mediated by a newly identified betaine-gated chloride channel, LGC-41, which is expressed broadly in the navigation circuit. These results implicate neuronally produced betaine as a neuromodulator in vivo and suggest a potentially similar role for betaine in nervous systems of other animals.
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Proteínas de Caenorhabditis elegans , Canales Iónicos Activados por Ligandos , Animales , Canales Iónicos Activados por Ligandos/genética , Betaína/farmacología , Betaína/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sistema Nervioso/metabolismoRESUMEN
The ability to perceive temperature is crucial for most animals. It enables them to maintain their body temperature and swiftly react to noxiously cold or hot objects. Caenorhabditis elegans is a powerful genetic model for the study of thermosensation as its simple nervous system is well characterized and its transparent body is suited for in vivo functional imaging of neurons. The behavior triggered by experience-dependent thermosensation has been well studied in C. elegans under temperature-gradient environments. However, how C. elegans senses temperature via its nervous system is not well understood due to the limitations of currently available technologies. One major bottleneck is the difficulty in creating fast temperature changes, especially cold stimuli. Here, we developed a microfluidic-based platform that allowed the in vivo functional imaging of C. elegans responding to well-controlled temporally varying temperature stimulation by rapidly switching fluid streams at different temperatures. We used computational models to enable rational design and optimization of experimental conditions. We validated the design and utility of our system with studies of the functional role of thermosensory neurons. We showed that the responses of PVD polymodal nociceptor neurons observed in previous studies can be recapitulated. Further, we highlighted how this platform may be used to dissect neuronal circuits with an example of activity recording in PVC interneurons. Both of these neuron types show sensitization phenotypes. We envision that both the engineered system and the findings in this work will spur further studies of molecular and cellular mechanisms underlying cold-sensing through the nervous system.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Temperatura , Caenorhabditis elegans/genética , Microfluídica , Sensación Térmica/fisiología , Frío , Proteínas de Caenorhabditis elegans/genéticaRESUMEN
Fast cholinergic neurotransmission is mediated by acetylcholine-gated ion channels; in particular, excitatory nicotinic acetylcholine receptors play well established roles in virtually all nervous systems. Acetylcholine-gated inhibitory channels have also been identified in some invertebrate phyla, yet their roles in the nervous system are less well understood. We report the existence of multiple new inhibitory ion channels with diverse ligand activation properties in Caenorhabditis elegans We identify three channels, LGC-40, LGC-57, and LGC-58, whose primary ligand is choline rather than acetylcholine, as well as the first evidence of a truly polymodal channel, LGC-39, which is activated by both cholinergic and aminergic ligands. Using our new ligand-receptor pairs we uncover the surprising extent to which single neurons in the hermaphrodite nervous system express both excitatory and inhibitory channels, not only for acetylcholine but also for the other major neurotransmitters. The results presented in this study offer new insight into the potential evolutionary benefit of a vast and diverse repertoire of ligand-gated ion channels to generate complexity in an anatomically compact nervous system.SIGNIFICANCE STATEMENT Here we describe the diversity of cholinergic signaling in the nematode Caenorhabditis elegans We identify and characterize a novel family of ligand-gated ion channels and show that they are preferentially gated by choline rather than acetylcholine and expressed broadly in the nervous system. Interestingly, we also identify one channel gated by chemically diverse ligands including acetylcholine and aminergic ligands. By using our new knowledge of these ligand-gated ion channels, we built a model to predict the synaptic polarity in the C. elegans connectome. This model can be used for generating hypotheses on neural circuit function.
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Canales Iónicos Activados por Ligandos , Receptores Nicotínicos , Animales , Caenorhabditis elegans/fisiología , Acetilcolina , Ligandos , Colinérgicos , ColinaRESUMEN
Acid-sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid sensitivity on all 30 subunits of the Caenorhabditis elegans DEG/ENaC family using two-electrode voltage clamp in Xenopus oocytes. We found two groups of acid-sensitive DEG/ENaCs characterised by being either inhibited or activated by increasing proton concentrations. Three of these acid-sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified three new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acid-sensitive channels. We observed sensitivity to the anti-hypertensive drug amiloride as well as modulation by the trace element zinc. Acid-sensitive DEG/ENaCs were found to be expressed in both neurons and non-neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid-sensing channels in vivo, as well as to study them as potential targets for anti-helminthic drugs. KEY POINTS: Acidosis plays many roles in healthy physiology, including synaptic transmission and gut function, but is also a key feature of inflammatory pain, ischaemia and many other conditions. Cells monitor acidosis of their surroundings via pH-sensing channels, including the acid-sensing ion channels (ASICs). These are members of the degenerin/epithelial sodium channel (DEG/ENaC) family, along with, as the name suggests, vertebrate ENaCs and degenerins of the roundworm Caenorhabditis elegans. By screening all 30 C. elegans DEG/ENaCs for pH dependence, we describe, for the first time, three acid-activated members, as well as three additional acid-inhibited channels. We surveyed both groups for sensitivity to amiloride and zinc; like their mammalian counterparts, their currents can be blocked, enhanced or unaffected by these modulators. Likewise, they exhibit diverse ion selectivity. Our findings underline the diversity of acid-sensitive DEG/ENaCs across species and provide a comparative resource for better understanding the molecular basis of their function.
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Caenorhabditis elegans , Canales Epiteliales de Sodio , Animales , Canales Epiteliales de Sodio/fisiología , Canales de Sodio Degenerina/fisiología , Canales Iónicos Sensibles al Ácido , Amilorida/farmacología , MamíferosRESUMEN
The DEG/ENaC family of ion channels was defined based on the sequence similarity between degenerins (DEG) from the nematode Caenorhabditis elegans and subunits of the mammalian epithelial sodium channel (ENaC), and also includes a diverse array of non-voltage-gated cation channels from across animal phyla, including the mammalian acid-sensing ion channels (ASICs) and Drosophila pickpockets. ENaCs and ASICs have wide ranging medical importance; for example, ENaCs play an important role in respiratory and renal function, and ASICs in ischaemia and inflammatory pain, as well as being implicated in memory and learning. Electrophysiological approaches, both in vitro and in vivo, have played an essential role in establishing the physiological properties of this diverse family, identifying an array of modulators and implicating them in an extensive range of cellular functions, including mechanosensation, acid sensation and synaptic modulation. Likewise, genetic studies in both invertebrates and vertebrates have played an important role in linking our understanding of channel properties to function at the cellular and whole animal/behavioural level. Drawing together genetic and physiological evidence is essential to furthering our understanding of the precise cellular roles of DEG/ENaC channels, with the diversity among family members allowing comparative physiological studies to dissect the molecular basis of these diverse functions.
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Canales Iónicos Sensibles al Ácido , Canales Epiteliales de Sodio , Animales , Canales Iónicos Sensibles al Ácido/genética , Canales Epiteliales de Sodio/metabolismo , Transducción de Señal , Caenorhabditis elegans/metabolismo , Drosophila/metabolismo , Mamíferos/metabolismoRESUMEN
Recent studies on the controllability of complex systems offer a powerful mathematical framework to systematically explore the structure-function relationship in biological, social, and technological networks. Despite theoretical advances, we lack direct experimental proof of the validity of these widely used control principles. Here we fill this gap by applying a control framework to the connectome of the nematode Caenorhabditis elegans, allowing us to predict the involvement of each C. elegans neuron in locomotor behaviours. We predict that control of the muscles or motor neurons requires 12 neuronal classes, which include neuronal groups previously implicated in locomotion by laser ablation, as well as one previously uncharacterized neuron, PDB. We validate this prediction experimentally, finding that the ablation of PDB leads to a significant loss of dorsoventral polarity in large body bends. Importantly, control principles also allow us to investigate the involvement of individual neurons within each neuronal class. For example, we predict that, within the class of DD motor neurons, only three (DD04, DD05, or DD06) should affect locomotion when ablated individually. This prediction is also confirmed; single cell ablations of DD04 or DD05 specifically affect posterior body movements, whereas ablations of DD02 or DD03 do not. Our predictions are robust to deletions of weak connections, missing connections, and rewired connections in the current connectome, indicating the potential applicability of this analytical framework to larger and less well-characterized connectomes.
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Caenorhabditis elegans/citología , Caenorhabditis elegans/fisiología , Conectoma , Red Nerviosa/citología , Red Nerviosa/fisiología , Neuronas/fisiología , Animales , Rayos Láser , Locomoción/fisiología , Neuronas Motoras/citología , Neuronas Motoras/fisiología , Neuronas/clasificaciónRESUMEN
Sleep, a state of quiescence associated with growth and restorative processes, is conserved across species. Invertebrates including the nematode Caenorhabditis elegans exhibit sleep-like states during development, satiety, and stress. Here, we describe behavior and neural activity during sleep and awake states in adult C. elegans hermaphrodites using new microfluidic methods. We observed effects of fluid flow, oxygen, feeding, odors, and genetic perturbations on long-term sleep behavior over 12 h. We developed a closed-loop sleep detection system to automatically deliver chemical stimuli to assess sleep-dependent changes to evoked neural responses in individual animals. Sleep increased the arousal threshold to aversive stimulation, yet the associated sensory neuron and first-layer interneuron responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the premotor interneurons, rather than afferent sensory circuits. However, sleep prolonged responses in appetitive chemosensory neurons, suggesting that sleep modulates responsiveness specifically across sensory systems rather than broadly damping global circuit activity.SIGNIFICANCE STATEMENT Much is known about molecular mechanisms that facilitate sleep control. However, it is unclear how these pathways modulate neural circuit-level sensory processing or how misregulation of neural activity contributes to sleep disorders. The nematode Caenorhabditis elegans provides the ability to study neural circuitry with single-neuron resolution, and recent studies examined sleep states between developmental stages and when stressed. Here, we examine an additional form of spontaneous sleep in adult C. elegans at the behavioral and neural activity levels. Using a closed-loop system, we show that delayed behavioral responses to aversive chemical stimulation during sleep arise from sleep-dependent sensorimotor modulation localized presynaptic to the premotor circuit, rather than early sensory circuits.
Asunto(s)
Neuronas/fisiología , Sueño/fisiología , Animales , Nivel de Alerta/fisiología , Conducta Animal/fisiología , Caenorhabditis elegansRESUMEN
Animals' perception and behavior involve integration of multiple sensory modalities. Caenorhabditis elegans is a useful model for studying multimodal sensory integration, as it has well-characterized neuronal circuits in a relatively simple nervous system. However, most studies based on functional imaging have only been conducted on single modal stimuli, because well-controlled multimodal experiments for C. elegans are technically difficult. For instance, no single systems currently deliver precise stimuli with spatial, temporal, and intensity control, despite prior hypotheses that interneurons do integrate these sensory inputs to control behavior. Here, a microfluidic platform that can easily deliver spatially and temporally controlled combination stimuli to C. elegans is presented. With this platform, both sensory and interneuron activity is measured in response to mechanical and chemical stimulations in a quantitative and high-throughput manner. It is found that the activity of command interneuron PVC can be modulated by prior stimulation both within the same and across different modalities. The roles of monoaminergic and peptidergic signaling are further examined on the process of multimodal integration through PVC activity. The approach exemplified here is envisioned to be broadly applicable in different contexts to elucidate underlying mechanisms and identify genes affecting multisensory integration.
Asunto(s)
Caenorhabditis elegans , Interneuronas , Microfluídica , Animales , Caenorhabditis elegans/fisiología , Interneuronas/fisiología , Microfluídica/instrumentación , Percepción/fisiologíaRESUMEN
Sensory loss induces cross-modal plasticity, often resulting in altered performance in remaining sensory modalities. Whereas much is known about the macroscopic mechanisms underlying cross-modal plasticity, only scant information exists about its cellular and molecular underpinnings. We found that Caenorhabditis elegans nematodes deprived of a sense of body touch exhibit various changes in behavior, associated with other unimpaired senses. We focused on one such behavioral alteration, enhanced odor sensation, and sought to reveal the neuronal and molecular mechanisms that translate mechanosensory loss into improved olfactory acuity. To this end, we analyzed in mechanosensory mutants food-dependent locomotion patterns that are associated with olfactory responses and found changes that are consistent with enhanced olfaction. The altered locomotion could be reversed in adults by optogenetic stimulation of the touch receptor (mechanosensory) neurons. Furthermore, we revealed that the enhanced odor response is related to a strengthening of inhibitory AWCâAIY synaptic transmission in the olfactory circuit. Consistently, inserting in this circuit an engineered electrical synapse that diminishes AWC inhibition of AIY counteracted the locomotion changes in touch-deficient mutants. We found that this cross-modal signaling between the mechanosensory and olfactory circuits is mediated by neuropeptides, one of which we identified as FLP-20. Our results indicate that under normal function, ongoing touch receptor neuron activation evokes FLP-20 release, suppressing synaptic communication and thus dampening odor sensation. In contrast, in the absence of mechanosensory input, FLP-20 signaling is reduced, synaptic suppression is released, and this enables enhanced olfactory acuity; these changes are long lasting and do not represent ongoing modulation, as revealed by optogenetic experiments. Our work adds to a growing literature on the roles of neuropeptides in cross-modal signaling, by showing how activity-dependent neuropeptide signaling leads to specific cross-modal plastic changes in neural circuit connectivity, enhancing sensory performance.
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Caenorhabditis elegans/fisiología , Células Quimiorreceptoras/fisiología , Mecanorreceptores/metabolismo , Neuropéptidos/fisiología , Olfato , Animales , Locomoción , Plasticidad Neuronal , Transmisión SinápticaRESUMEN
Transmembrane channel-like (TMC) genes encode a broadly conserved family of multipass integral membrane proteins in animals. Human TMC1 and TMC2 genes are linked to human deafness and required for hair-cell mechanotransduction; however, the molecular functions of these and other TMC proteins have not been determined. Here we show that the Caenorhabditis elegans tmc-1 gene encodes a sodium sensor that functions specifically in salt taste chemosensation. tmc-1 is expressed in the ASH polymodal avoidance neurons, where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl. However, tmc-1 has no effect on responses to other stimuli sensed by the ASH neurons including high osmolarity and chemical repellents, indicating a specific role in salt sensation. When expressed in mammalian cell culture, C. elegans TMC-1 generates a predominantly cationic conductance activated by high extracellular sodium but not by other cations or uncharged small molecules. Thus, TMC-1 is both necessary for salt sensation in vivo and sufficient to generate a sodium-sensitive channel in vitro, identifying it as a probable ionotropic sensory receptor.
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Caenorhabditis elegans/fisiología , Canales Iónicos/metabolismo , Cloruro de Sodio/metabolismo , Gusto/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Células CHO , Caenorhabditis elegans/efectos de los fármacos , Cricetinae , Conductividad Eléctrica , Canales Iónicos/agonistas , Canales Iónicos/genética , Concentración Osmolar , Cloruro de Sodio/farmacología , Gusto/efectos de los fármacosRESUMEN
C. elegans undergoes periods of behavioral quiescence during larval molts (termed lethargus) and as adults. Little is known about the circuit mechanisms that establish these quiescent states. Lethargus and adult locomotion quiescence is dramatically reduced in mutants lacking the neuropeptide receptor NPR-1. Here, we show that the aroused locomotion of npr-1 mutants results from the exaggerated activity in multiple classes of sensory neurons, including nociceptive (ASH), touch sensitive (ALM and PLM), and stretch sensing (DVA) neurons. These sensory neurons accelerate locomotion via both neuropeptide and glutamate release. The relative contribution of these sensory neurons to arousal differs between larval molts and adults. Our results suggest that a broad network of sensory neurons dictates transitions between aroused and quiescent behavioral states.
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Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Movimiento Celular/fisiología , Ácido Glutámico/metabolismo , Neuropéptidos/metabolismo , Receptores de Neuropéptido Y/genética , Células Receptoras Sensoriales/metabolismo , Animales , Nivel de Alerta/fisiología , Conducta Animal/fisiología , Caenorhabditis elegans/metabolismo , Nociceptores/metabolismo , Sueño/fisiologíaRESUMEN
Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways.
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Adaptación Fisiológica/fisiología , Conducta Alimentaria/fisiología , Neuropéptidos/metabolismo , Nocicepción/fisiología , Transducción de Señal/fisiología , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Animales , Animales Modificados Genéticamente , Células CHO , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Transportador de Aminoácidos Catiônicos 2/genética , Transportador de Aminoácidos Catiônicos 2/metabolismo , Cobre/farmacología , Cricetulus , Dopamina/genética , Dopamina/metabolismo , Ayuno , Nocicepción/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Connectomics has focused primarily on the mapping of synaptic links in the brain; yet it is well established that extrasynaptic volume transmission, especially via monoamines and neuropeptides, is also critical to brain function and occurs primarily outside the synaptic connectome. We have mapped the putative monoamine connections, as well as a subset of neuropeptide connections, in C. elegans based on new and published gene expression data. The monoamine and neuropeptide networks exhibit distinct topological properties, with the monoamine network displaying a highly disassortative star-like structure with a rich-club of interconnected broadcasting hubs, and the neuropeptide network showing a more recurrent, highly clustered topology. Despite the low degree of overlap between the extrasynaptic (or wireless) and synaptic (or wired) connectomes, we find highly significant multilink motifs of interaction, pinpointing locations in the network where aminergic and neuropeptide signalling modulate synaptic activity. Thus, the C. elegans connectome can be mapped as a multiplex network with synaptic, gap junction, and neuromodulator layers representing alternative modes of interaction between neurons. This provides a new topological plan for understanding how aminergic and peptidergic modulation of behaviour is achieved by specific motifs and loci of integration between hard-wired synaptic or junctional circuits and extrasynaptic signals wirelessly broadcast from a small number of modulatory neurons.
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Caenorhabditis elegans/fisiología , Conectoma , Animales , Monoaminas Biogénicas , Biología Computacional , Transducción de SeñalRESUMEN
Using low-cost automated tracking microscopes, we have generated a behavioral database for 305 Caenorhabditis elegans strains, including 76 mutants with no previously described phenotype. The growing database currently consists of 9,203 short videos segmented to extract behavior and morphology features, and these videos and feature data are available online for further analysis. The database also includes summary statistics for 702 measures with statistical comparisons to wild-type controls so that phenotypes can be identified and understood by users.
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Conducta Animal , Caenorhabditis elegans/fisiología , Bases de Datos Factuales , Grabación en Video/métodos , Algoritmos , Animales , Caenorhabditis elegans/genética , Mutación , Fenotipo , Reproducibilidad de los Resultados , Grabación en Video/instrumentaciónRESUMEN
Locomotion is driven by shape changes coordinated by the nervous system through time; thus, enumerating an animal's complete repertoire of shape transitions would provide a basis for a comprehensive understanding of locomotor behaviour. Here we introduce a discrete representation of behaviour in the nematode C. elegans. At each point in time, the worm's posture is approximated by its closest matching template from a set of 90 postures and locomotion is represented as sequences of postures. The frequency distribution of postural sequences is heavy-tailed with a core of frequent behaviours and a much larger set of rarely used behaviours. Responses to optogenetic and environmental stimuli can be quantified as changes in postural syntax: worms show different preferences for different sequences of postures drawn from the same set of templates. A discrete representation of behaviour will enable the use of methods developed for other kinds of discrete data in bioinformatics and language processing to be harnessed for the study of behaviour.
Asunto(s)
Caenorhabditis elegans/fisiología , Locomoción/fisiología , Animales , Conducta Animal , Análisis por Conglomerados , Biología Computacional , OptogenéticaRESUMEN
Spatially embedded complex networks, such as nervous systems, the Internet, and transportation networks, generally have nontrivial topological patterns of connections combined with nearly minimal wiring costs. However, the growth rules shaping these economical tradeoffs between cost and topology are not well understood. Here, we study the cellular nervous system of the nematode worm Caenorhabditis elegans, together with information on the birth times of neurons and on their spatial locations. We find that the growth of this network undergoes a transition from an accelerated to a constant increase in the number of links (synaptic connections) as a function of the number of nodes (neurons). The time of this phase transition coincides closely with the observed moment of hatching, when development switches metamorphically from oval to larval stages. We use graph analysis and generative modeling to show that the transition between different growth regimes, as well as its coincidence with the moment of hatching, may be explained by a dynamic economical model that incorporates a tradeoff between topology and cost that is continuously negotiated and renegotiated over developmental time. As the body of the animal progressively elongates, the cost of longer-distance connections is increasingly penalized. This growth process regenerates many aspects of the adult nervous system's organization, including the neuronal membership of anatomically predefined ganglia. We expect that similar economical principles may be found in the development of other biological or manmade spatially embedded complex systems.
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Caenorhabditis elegans/fisiología , Modelos Neurológicos , Animales , Simulación por Computador , Uniones Comunicantes/fisiología , Modelos Lineales , Método de Montecarlo , Red Nerviosa/fisiología , Sistema Nervioso , Neuronas/metabolismo , Neuronas/fisiología , Probabilidad , Factores de TiempoRESUMEN
Visible phenotypes based on locomotion and posture have played a critical role in understanding the molecular basis of behavior and development in Caenorhabditis elegans and other model organisms. However, it is not known whether these human-defined features capture the most important aspects of behavior for phenotypic comparison or whether they are sufficient to discover new behaviors. Here we show that four basic shapes, or eigenworms, previously described for wild-type worms, also capture mutant shapes, and that this representation can be used to build a dictionary of repetitive behavioral motifs in an unbiased way. By measuring the distance between each individual's behavior and the elements in the motif dictionary, we create a fingerprint that can be used to compare mutants to wild type and to each other. This analysis has revealed phenotypes not previously detected by real-time observation and has allowed clustering of mutants into related groups. Behavioral motifs provide a compact and intuitive representation of behavioral phenotypes.
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Conducta Animal/fisiología , Caenorhabditis elegans/genética , Genes/genética , Locomoción/genética , Modelos Biológicos , Fenotipo , Animales , Conducta Animal/clasificación , Caenorhabditis elegans/clasificación , Caenorhabditis elegans/fisiología , Genética Conductual/métodos , Locomoción/fisiología , Reconocimiento de Normas Patrones Automatizadas/métodos , Postura/fisiología , Reproducibilidad de los ResultadosRESUMEN
CLC-2 is a hyperpolarization-activated, inwardly rectifying chloride channel. Although the properties of the CLC-2 channel have been well characterized, its function in vivo is not well understood. We have found that channels encoded by the Caenorhabditis elegans CLC-2 homolog clh-3 regulate the activity of the spontaneously active hermaphrodite-specific neurons (HSNs), which control the egg-laying behavior. We identified a gain-of-function mutation in clh-3 that increases channel activity. This mutation inhibits egg laying and inhibits HSN activity by decreasing its excitability. Conversely, loss-of-function mutations in clh-3 lead to misregulated egg laying and an increase in HSN excitability, indicating that these channels modulate egg laying by limiting HSN excitability. clh-3-encoded channels are not required for GABAA-receptor-mediated inhibition of the HSN. However, they require low intracellular chloride for HSN inhibition, indicating that they inhibit excitability directly by mediating chloride influx. This mechanism of CLH-3-dependent modulation may be conserved in other neurons in which the driving force favors chloride influx.