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1.
Elife ; 112022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36378164

RESUMO

Precise synaptic connection of neurons with their targets is essential for the proper functioning of the nervous system. A plethora of signaling pathways act in concert to mediate the precise spatial arrangement of synaptic connections. Here we show a novel role for a gap junction protein in controlling tiled synaptic arrangement in the GABAergic motor neurons in Caenorhabditis elegans, in which their axons and synapses overlap minimally with their neighboring neurons within the same class. We found that while EGL-20/Wnt controls axonal tiling, their presynaptic tiling is mediated by a gap junction protein UNC-9/Innexin, that is localized at the presynaptic tiling border between neighboring dorsal D-type GABAergic motor neurons. Strikingly, the gap junction channel activity of UNC-9 is dispensable for its function in controlling tiled presynaptic patterning. While gap junctions are crucial for the proper functioning of the nervous system as channels, our finding uncovered the novel channel-independent role of UNC-9 in synapse patterning.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Sinapses/metabolismo , Neurônios Motores/metabolismo , Conexinas/genética , Conexinas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo
2.
Sensors (Basel) ; 22(22)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36433423

RESUMO

Caenorhabditis elegans (C. elegans) exhibits sophisticated chemotaxis behavior with a unique locomotion pattern using a simple nervous system only and is, therefore, well suited to inspire simple, cost-effective robotic navigation schemes. Chemotaxis in C. elegans involves two complementary strategies: klinokinesis, which allows reorientation by sharp turns when moving away from targets; and klinotaxis, which gradually adjusts the direction of motion toward the preferred side throughout the movement. In this study, we developed an autonomous search model with undulatory locomotion that combines these two C. elegans chemotaxis strategies with its body undulatory locomotion. To search for peaks in environmental variables such as chemical concentrations and radiation in directions close to the steepest gradients, only one sensor is needed. To develop our model, we first evolved a central pattern generator and designed a minimal network unit with proprioceptive feedback to encode and propagate rhythmic signals; hence, we realized realistic undulatory locomotion. We then constructed adaptive sensory neuron models following real electrophysiological characteristics and incorporated a state-dependent gating mechanism, enabling the model to execute the two orientation strategies simultaneously according to information from a single sensor. Simulation results verified the effectiveness, superiority, and realness of the model. Our simply structured model exploits multiple biological mechanisms to search for the shortest-path concentration peak over a wide range of gradients and can serve as a theoretical prototype for worm-like navigation robots.


Assuntos
Caenorhabditis elegans , Locomoção , Animais , Caenorhabditis elegans/fisiologia , Locomoção/fisiologia , Redes Neurais de Computação , Quimiotaxia , Simulação por Computador
3.
Prog Mol Biol Transl Sci ; 193(1): 119-144, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36357074

RESUMO

The past decades have witnessed a dogmatic shift from glia as supporting cells in the nervous system to their active roles in neurocentric functions. Neurons and glia communicate and show bidirectional responses through tripartite synapses. Studies across species indicate that neurotransmitters released by neurons are perceived by glial receptors, which allow for gliotransmitter release. These gliotransmitters can result in activation of neurons via neuronal GPCR receptors. However, studies of these molecular interactions are in their infancy. Caenorhabditis elegans has a conserved neuron-glia architectural repertoire with molecular and functional resemblance to mammals. Further, glia in C. elegans can be manipulated through ablation and mutations allowing for deciphering of glial dependent processes in vivo at single glial resolutions. Here, we will review recent findings from vertebrate and invertebrate organisms with a focus on how C. elegans can be used to advance our understanding of neuron-glia interactions through GPCRs.


Assuntos
Caenorhabditis elegans , Neuroglia , Humanos , Animais , Caenorhabditis elegans/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Receptores Acoplados a Proteínas G , Mamíferos
4.
Elife ; 112022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36226814

RESUMO

Hydrogen peroxide is the most common reactive chemical that organisms face on the microbial battlefield. The rate with which hydrogen peroxide damages biomolecules required for life increases with temperature, yet little is known about how organisms cope with this temperature-dependent threat. Here, we show that Caenorhabditis elegans nematodes use temperature information perceived by sensory neurons to cope with the temperature-dependent threat of hydrogen peroxide produced by the pathogenic bacterium Enterococcus faecium. These nematodes preemptively induce the expression of specific hydrogen peroxide defenses in response to perception of high temperature by a pair of sensory neurons. These neurons communicate temperature information to target tissues expressing those defenses via an insulin/IGF1 hormone. This is the first example of a multicellular organism inducing their defenses to a chemical when they sense an inherent enhancer of the reactivity of that chemical.


The Earth's environment is full of reactive chemicals that can cause harm to organisms. One of the most common is hydrogen peroxide, which is produced by several bacteria in concentrations high enough to kill small animals, such as the roundworm Caenorhabditis elegans. Forced to live in close proximity to such perils, C. elegans have evolved defenses to ensure their survival, such as producing enzymes that can break down hydrogen peroxide. However, this battle is compounded by other factors. For instance, rising temperatures can increase the rate at which the hydrogen peroxide produced by bacteria reacts with the molecules and proteins of C. elegans. In 2020, a group of researchers found that roundworms sense these temperature changes through special cells called sensory neurons and use this information to control the generation of enzymes that break down hydrogen peroxide. This suggests that C. elegans may pre-emptively prepare their defenses against hydrogen peroxide in response to higher temperatures so they are better equipped to shield themselves from this harmful chemical. To test this theory, Servello et al. ­ including some of the authors involved in the 2020 study ­ exposed C. elegans to a species of bacteria that produces hydrogen peroxide. This revealed that the roundworms were better at dealing with the threat of hydrogen peroxide when growing in warmer temperatures. Experiments done in C. elegans lacking a class of sensory cells, the AFD neurons, showed that these neurons increased the roundworms' resistance to the chemical when temperatures increase. They do this by repressing the activity of INS-39, a hormone that stops C. elegans from switching on their defense mechanism against peroxides. This is the first example of a multicellular organism preparing its defenses to a chemical after sensing something (such as temperature) that enhances its reactivity. It is possible that other animals may also use this 'enhancer sensing' strategy to anticipate and shield themselves from hydrogen peroxide and potentially other external threats.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Peróxido de Hidrogênio/metabolismo , Temperatura , Proteínas de Caenorhabditis elegans/metabolismo , Células Receptoras Sensoriais/metabolismo , Percepção
5.
Curr Biol ; 32(21): 4631-4644.e5, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36182701

RESUMO

In many animals, there is a direct correspondence between the motor patterns that drive locomotion and the motor neuron innervation. For example, the adult C. elegans moves with symmetric and alternating dorsal-ventral bending waves arising from symmetric motor neuron input onto the dorsal and ventral muscles. In contrast to the adult, the C. elegans motor circuit at the juvenile larval stage has asymmetric wiring between motor neurons and muscles but still generates adult-like bending waves with dorsal-ventral symmetry. We show that in the juvenile circuit, wiring between excitatory and inhibitory motor neurons coordinates the contraction of dorsal muscles with relaxation of ventral muscles, producing dorsal bends. However, ventral bending is not driven by analogous wiring. Instead, ventral muscles are excited uniformly by premotor interneurons through extrasynaptic signaling. Ventral bends occur in anti-phasic entrainment to activity of the same motor neurons that drive dorsal bends. During maturation, the juvenile motor circuit is replaced by two motor subcircuits that separately drive dorsal and ventral bending. Modeling reveals that the juvenile's immature motor circuit is an adequate solution to generate adult-like dorsal-ventral bending before the animal matures. Developmental rewiring between functionally degenerate circuit solutions, which both generate symmetric bending patterns, minimizes behavioral disruption across maturation.


Assuntos
Caenorhabditis elegans , Neurônios Motores , Animais , Caenorhabditis elegans/fisiologia , Neurônios Motores/fisiologia , Interneurônios/fisiologia , Locomoção/fisiologia , Larva/fisiologia
6.
BMC Biol ; 20(1): 229, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209082

RESUMO

BACKGROUND: Altering animal behavior to reduce pathogen exposure is a key line of defense against pathogen attack. In Caenorhabditis elegans, alterations in intestinal physiology caused by pathogen colonization and sensation of microbial metabolites may lead to activation of pathogen aversive behaviors ranging from aversive reflexes to learned avoidance. However, the neural circuitry between chemosensory neurons that sense pathogenic bacterial cues and the motor neurons responsible for avoidance-associated locomotion remains unknown. RESULTS: Using C. elegans, we found that backward locomotion was a component of learned pathogen avoidance, as animals pre-exposed to Pseudomonas aeruginosa or Enterococcus faecalis showed reflexive aversion to drops of the bacteria driven by chemosensory neurons, including the olfactory AWB neurons. This response also involved intestinal distention and, for E. faecalis, required expression of TRPM channels in the intestine and excretory system. Additionally, we uncovered a circuit composed of olfactory neurons, interneurons, and motor neurons that controls the backward locomotion crucial for learned reflexive aversion to pathogenic bacteria, learned avoidance, and the repulsive odor 2-nonanone. CONCLUSIONS: Using whole-brain simulation and functional assays, we uncovered a novel sensorimotor circuit governing learned reflexive aversion. The discovery of a complete sensorimotor circuit for reflexive aversion demonstrates the utility of using the C. elegans connectome and computational modeling in uncovering new neuronal regulators of behavior.


Assuntos
Proteínas de Caenorhabditis elegans , Canais de Cátion TRPM , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Pseudomonas aeruginosa , Olfato/fisiologia
7.
PLoS One ; 17(10): e0271849, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36256641

RESUMO

Alcohol abuse and dependence have a substantial heritable component. Although the genome has been considered the sole vehicle of heritable phenotypes, recent studies suggest that drug or alcohol exposure may induce alterations in gene expression that are transmitted across generations. Still, the transgenerational impact of alcohol use (and abuse) remains largely unexplored in part because multigenerational studies using rodent models present challenges for time, sample size, and genetic heterogeneity. Here, we took advantage of the extremely short generation time, large broods, and clonal form of reproduction of the nematode Caenorhabditis elegans. We developed a model of pre-fertilization parental alcohol exposure to test alterations in behavioral responses to acute alcohol treatment (referred to in short as intoxication) in subsequent F1, F2 and F3 generations. We found that chronic and intermittent alcohol-treatment paradigms resulted in opposite changes to intoxication sensitivity of F3 progeny that were only apparent when controlling for yoked trials. Chronic alcohol-treatment paradigm in the parental generation resulted in alcohol-naïve F3 progeny displaying moderate resistance to intoxication. Intermittent treatment resulted in alcohol-naïve F3 progeny displaying moderate hypersensitivity to intoxication. Further study of these phenomena using this new C. elegans model may yield mechanistic insights into how transgenerational effects may occur in other animals.


Assuntos
Caenorhabditis elegans , Reprodução , Animais , Caenorhabditis elegans/fisiologia , Etanol/toxicidade , Consumo de Bebidas Alcoólicas
8.
Nutrients ; 14(19)2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36235629

RESUMO

Queen bee larva (QBL) is one kind of important edible insect that is harvested during royal jelly production process. QBL has many physiological functions; however, limited information is available regarding its antiaging effects. In this study, the antiaging function of freeze-dried QBL powder (QBLP) was investigated by combining the Caenorhabditis elegans (C. elegans) model and transcriptomics. The administration of QBLP to C. elegans was shown to improve lifespan parameters. Additionally, QBLP improved the mobility of nematodes. Transcriptome analysis showed the differentially expressed genes (DEGs) were significantly enriched in Gene Ontology (GO) terms that were almost all related to the biological functions of cell metabolism and stress, which are associated with lifespan. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the lifespan of C. elegans was related to the longevity regulating pathway-worm. The expression levels of the key genes sod-3, gst-6, hsp-12.6, lips-7, ins-8, and lips-17 were upregulated. sod-3, hsp-12.6, lips-7, and lips-17 are downstream targets of DAF-16, which is an important transcription factor related to lifespan extension. CF1038 (daf-16(mu86)) supplemented with QBLP did not show a life-prolonging. This indicates that the antiaging function of QBLP is closely related to daf-16. Thus, QBLP is a component that could potentially be used as a functional material to ameliorate aging and aging-related symptoms.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Abelhas , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Suplementos Nutricionais , Fatores de Transcrição Forkhead/metabolismo , Larva , Longevidade/fisiologia , Estresse Oxidativo , Pós
9.
J Neurosci ; 42(46): 8599-8607, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36302635

RESUMO

Neuropeptide release from dense-core vesicles in Caenorhabditis elegans is promoted by UNC-31, ortholog of the calcium-dependent activator protein for secretion (CAPS). Loss of UNC-31 causes multiple phenotypes in C. elegans including reduced motility, retention of late-stage eggs, and reduction in evoked synaptic release. However, the ability to analyze UNC-31 function over discrete timescales and in specific neurons is lacking. Here, we generated and validated a tool to enable UNC-31 expression and spatiotemporal functional analysis. We show that endogenously tagged UNC-31 is expressed in major ganglia and nerve cords from late embryonic stages through to adult. Using the auxin-inducible degradation system, we depleted UNC-31 postembryonically from the hermaphrodite nervous system and revealed defects in egg laying, locomotion, and vesicle release that were comparable to those in unc-31 null mutant animals. In addition, we found that depleting UNC-31 specifically from the BAG sensory neurons causes increased intestinal fat storage, highlighting the spatial sensitivity of this system. Together, this protein degradation tool may be used to facilitate studies of neuropeptide function at precise cellular and temporal scales.SIGNIFICANCE STATEMENT Animal behavior and physiology is controlled by neuropeptides that are released from specific neuronal sources. The ability to dissect discrete neuropeptide functions requires precise manipulation of neuropeptide release. We have developed and validated a tool that enables precise spatiotemporal regulation of neuropeptide release that will enable researchers to examine neuropeptide function at exceptional resolution.


Assuntos
Proteínas de Caenorhabditis elegans , Neuropeptídeos , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Neurônios/metabolismo , Análise Espaço-Temporal , Mutação
10.
Curr Biol ; 32(21): 4645-4659.e3, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36283410

RESUMO

During development, animals can maintain behavioral output even as underlying circuitry structurally remodels. After hatching, C. elegans undergoes substantial motor neuron expansion and synapse rewiring while the animal continuously moves with an undulatory pattern. To understand how the circuit transitions from its juvenile to mature configuration without interrupting functional output, we reconstructed the C. elegans motor circuit by electron microscopy across larval development. We observed the following: First, embryonic motor neurons transiently interact with the developing post-embryonic motor neurons prior to remodeling of their juvenile wiring. Second, post-embryonic neurons initiate synapse development with their future partners as their neurites navigate through the juvenile nerve cords. Third, embryonic and post-embryonic neurons sequentially build structural machinery needed for the adult circuit before the embryonic neurons relinquish their roles to post-embryonic neurons. Fourth, this transition is repeated region by region along the body in an anterior-to-posterior sequence, following the birth order of neurons. Through this orchestrated and programmed rewiring, the motor circuit gradually transforms from asymmetric to symmetric wiring. These maturation strategies support the continuous maintenance of motor patterns as the juvenile circuit develops into the adult configuration.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Neurônios Motores/fisiologia , Sinapses/fisiologia , Neuritos , Proteínas de Caenorhabditis elegans/genética
11.
Cell Rep ; 41(2): 111473, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36223742

RESUMO

Nutrient availability governs growth and quiescence, and many animals arrest development when starved. Using C. elegans L1 arrest as a model, we show that gene expression changes deep into starvation. Surprisingly, relative expression of germline-enriched genes increases for days. We conditionally degrade the large subunit of RNA polymerase II using the auxin-inducible degron system and analyze absolute expression levels. We find that somatic transcription is required for survival, but the germline maintains transcriptional quiescence. Thousands of genes are continuously transcribed in the soma, though their absolute abundance declines, such that relative expression of germline transcripts increases given extreme transcript stability. Aberrantly activating transcription in starved germ cells compromises reproduction, demonstrating important physiological function of transcriptional quiescence. This work reveals alternative somatic and germline gene-regulatory strategies during starvation, with the soma maintaining a robust transcriptional response to support survival and the germline maintaining transcriptional quiescence to support future reproductive success.


Assuntos
Proteínas de Caenorhabditis elegans , Inanição , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células Germinativas/metabolismo , Ácidos Indolacéticos/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Inanição/metabolismo
12.
PLoS Comput Biol ; 18(10): e1010594, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36215325

RESUMO

Advanced volumetric imaging methods and genetically encoded activity indicators have permitted a comprehensive characterization of whole brain activity at single neuron resolution in Caenorhabditis elegans. The constant motion and deformation of the nematode nervous system, however, impose a great challenge for consistent identification of densely packed neurons in a behaving animal. Here, we propose a cascade solution for long-term and rapid recognition of head ganglion neurons in a freely moving C. elegans. First, potential neuronal regions from a stack of fluorescence images are detected by a deep learning algorithm. Second, 2-dimensional neuronal regions are fused into 3-dimensional neuron entities. Third, by exploiting the neuronal density distribution surrounding a neuron and relative positional information between neurons, a multi-class artificial neural network transforms engineered neuronal feature vectors into digital neuronal identities. With a small number of training samples, our bottom-up approach is able to process each volume-1024 × 1024 × 18 in voxels-in less than 1 second and achieves an accuracy of 91% in neuronal detection and above 80% in neuronal tracking over a long video recording. Our work represents a step towards rapid and fully automated algorithms for decoding whole brain activity underlying naturalistic behaviors.


Assuntos
Encéfalo , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Encéfalo/fisiologia , Neurônios/fisiologia
13.
Toxicol Ind Health ; 38(10): 665-674, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36062628

RESUMO

Accumulating evidence has shown that bisphenol A (BPA) affects not only the growth and development of reproductive tissues but also disrupts meiosis. Meiotic disturbances lead to the formation of aneuploid gametes, resulting in the inability to conceive, pregnancy loss, and developmental disabilities in offspring. In recent years, increasing health concerns led manufacturers to seek BPA alternatives. In response, BPA analogs have been prepared and investigated in a variety of toxicity-related studies. Despite hopes that these analogs would prove less harmful than BPA, published data show that these alternatives continue to pose a significant risk to human health. In this study, we synthesized two less investigated BPA analogs with cyclic side chains, bisphenol Y (BPY) and bisphenol Z (BPZ), and evaluated their reprotoxic potential using Caenorhabditis elegans. C. elegans were cultured on nematode growth medium plates containing a 1 mM concentration of the dimethyl sulfoxide-dissolved bisphenols. The uptake of the chemicals was via two major routes: ingestion and cuticle diffusion. Following exposure, we evaluated fertilized egg count, germline apoptosis, and embryonic lethality-three parameters previously shown to reliably predict the reprotoxic potential of bisphenols in mammals. Our results indicated that both BPY and BPZ had a significant impact on fertility, resulting in increased germline apoptosis and a reduced number of progeny, without affecting the embryonic viability. After comparison with commercially relevant BPA and bisphenol S, our findings imply that BPA analogs with cyclic side chains, BPY and BPZ, adversely affect meiotic fidelity, resulting in diminished reproductive capacity.


Assuntos
Caenorhabditis elegans , Dimetil Sulfóxido , Animais , Compostos Benzidrílicos/toxicidade , Caenorhabditis elegans/fisiologia , Cicloexanos , Feminino , Humanos , Mamíferos , Fenóis , Gravidez
14.
Curr Biol ; 32(20): 4372-4385.e7, 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36075218

RESUMO

The effect of the detailed connectivity of a neural circuit on its function and the resulting behavior of the organism is a key question in many neural systems. Here, we study the circuit for nociception in C. elegans, which is composed of the same neurons in the two sexes that are wired differently. We show that the nociceptive sensory neurons respond similarly in the two sexes, yet the animals display sexually dimorphic behaviors to the same aversive stimuli. To uncover the role of the downstream network topology in shaping behavior, we learn and simulate network models that replicate the observed dimorphic behaviors and use them to predict simple network rewirings that would switch behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Interestingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that network topologies that enable efficient avoidance of noxious cues have a reproductive "cost." Our results present a deconstruction of the design of a neural circuit that controls sexual behavior and how to reprogram it.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Masculino , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Nociceptividade , Sistema Nervoso , Células Receptoras Sensoriais/fisiologia
15.
Sci Rep ; 12(1): 15310, 2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130988

RESUMO

Despite its physiological and pathological importance, the mechanical relationship between glucose uptake in the intestine and intestinal flows is unclear. In the intestine of the nematode Caenorhabditis elegans, the defecation motor program (DMP) causes reciprocating intestinal flows. Although the DMP is frequently activated in the intestines, its physiological function is unknown. We evaluated the mechanical signature of enhanced glucose uptake by the DMP in worms. Glucose uptake tended to increase with increasing flow velocity during the DMP because of mechanical mixing and transport. However, the increase in input energy required for the DMP was low compared with the calorie intake. The findings suggest that animals with gastrointestinal motility exploit the reciprocating intestinal flows caused by peristalsis to promote nutrient absorption by intestinal cells.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Motilidade Gastrointestinal , Glucose , Intestinos/fisiologia
16.
Sci Rep ; 12(1): 16108, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167800

RESUMO

Ageing is co-regulated by genetic and environmental factors. Life on earth lives and evolves in a mild geomagnetic field. Yet, the biological effects of a moderate magnetic field on ageing and the underlying genetic mechanisms remain barely unknown. Here, we report that a moderate static magnetic field (SMF) extends the lifespan of Caenorhabditis elegans, a well-established model organism in ageing research. Consistently, the SMF-treated worms show improved motility and mitochondrial function when aged. We identified from the transcriptomic changes upon SMF treatment that the upregulation of three cytochrome P450 genes are required for SMF-induced longevity. Our findings thus reveal that proper SMF treatment could promote longevity through the well-conserved cytochrome P450 enzymes.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Sistema Enzimático do Citocromo P-450/genética , Longevidade/genética , Campos Magnéticos
17.
J Neurosci ; 42(43): 8039-8053, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36104280

RESUMO

Proper management of memories by forgetting and retrieval is essential for animals to adapt their behavior to changing environments. To elucidate the mechanisms underlying forgetting, we use olfactory learning to an attractive odorant, diacetyl, in Caenorhabditis elegans hermaphrodites as a model. In this learning paradigm, the TIR-1/JNK-1 pathway in AWC sensory neurons accelerates forgetting of the olfactory memory, which is stored as a sensory memory trace in AWA sensory neurons. Our genetic screening revealed that increased neuronal diacylglycerol in the olfactory neuronal circuit, by mutations in diacylglycerol kinase-1, egl-30 or goa-1, Gq and Go type G-proteins, suppresses the forgetting defect in the behavior of tir-1 mutants, although the calcium imaging analyses of the olfactory neurons revealed that the sensory memory trace to the odorant was maintained. In contrast, the expression of a gain-of-function goa-1 gene exclusively in AWC neurons caused a forgetting defect in behavior, although their sensory memory trace declined. Furthermore, the behavioral analysis of animals applied with diacylglycerol analog and measurement of diacylglycerol content by fluorescent imaging suggested that diacylglycerol content in AWC is important for the proper forgetting. These findings raise a possibility that diacylglycerol signaling plays a crucial role in determining whether to forget or to recall in olfactory learning.SIGNIFICANCE STATEMENT Forgetting and retrieval are important processes for proper management of memories, although the mechanisms underlying these processes remain largely unclear. We found that, in Caenorhabditis elegans, diacylglycerol signaling works in a forgetting mechanism downstream of TIR-1/JNK-1 pathway. Mutations that change diacylglycerol content in the olfactory neurons affect behavioral forgetting, although they did not alter the sensory memory trace. This suggests that diacylglycerol in specific neurons may determine the occurrence of retrieving, rather than modifying, the memory traces. Consistent with this hypothesis, application of diacylglycerol analog to animals suggests that diacylglycerol content until memory acquisition decides whether to retrieve or to forget the memory.


Assuntos
Proteínas de Caenorhabditis elegans , Neurônios Receptores Olfatórios , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Cálcio/metabolismo , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Diglicerídeos/metabolismo , Diacetil , Olfato/fisiologia , Proteínas de Ligação ao GTP , Células Receptoras Sensoriais/metabolismo , Neurônios Receptores Olfatórios/fisiologia
18.
Elife ; 112022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35968765

RESUMO

Animal development requires coordination among cyclic processes, sequential cell fate specifications, and once-a-lifetime morphogenic events, but the underlying timing mechanisms are not well understood. Caenorhabditis elegans undergoes four molts at regular 8 to 10 hour intervals. The pace of the cycle is governed by PERIOD/lin-42 and other as-yet unknown factors. Cessation of the cycle in young adults is controlled by the let-7 family of microRNAs and downstream transcription factors in the heterochronic pathway. Here, we characterize a negative feedback loop between NHR-23, the worm homolog of mammalian retinoid-related orphan receptors (RORs), and the let-7 family of microRNAs that regulates both the frequency and finite number of molts. The molting cycle is decelerated in nhr-23 knockdowns and accelerated in let-7(-) mutants, but timed similarly in let-7(-) nhr-23(-) double mutants and wild-type animals. NHR-23 binds response elements (ROREs) in the let-7 promoter and activates transcription. In turn, let-7 dampens nhr-23 expression across development via a complementary let-7-binding site (LCS) in the nhr-23 3' UTR. The molecular interactions between NHR-23 and let-7 hold true for other let-7 family microRNAs. Either derepression of nhr-23 transcripts by LCS deletion or high gene dosage of nhr-23 leads to protracted behavioral quiescence and extra molts in adults. NHR-23 and let-7 also coregulate scores of genes required for execution of the molts, including lin-42. In addition, ROREs and LCSs isolated from mammalian ROR and let-7 genes function in C. elegans, suggesting conservation of this feedback mechanism. We propose that this feedback loop unites the molting timer and the heterochronic gene regulatory network, possibly by functioning as a cycle counter.


Assuntos
Proteínas de Caenorhabditis elegans , MicroRNAs , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Retroalimentação , Regulação da Expressão Gênica no Desenvolvimento , Mamíferos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Muda/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/metabolismo , Retinoides/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Elife ; 112022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35929733

RESUMO

The phagocytic receptor CED-1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in Caenorhabditis elegans. Whether appropriate levels of CED-1 are maintained for executing the engulfment function remains unknown. Here, we identified the C. elegans E3 ubiquitin ligase tripartite motif containing-21 (TRIM-21) as a component of the CED-1 pathway for apoptotic cell clearance. When the NPXY motif of CED-1 was bound to the adaptor protein CED-6 or the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1 and subsequently bound to the adaptor protein NCK-1 containing the SH2 domain, TRIM-21 functioned in conjunction with UBC-21 to catalyze K48-linked poly-ubiquitination on CED-1, targeting it for proteasomal degradation. In the absence of TRIM-21, CED-1 accumulated post-translationally and drove cell corpse degradation defects, as evidenced by direct binding to VHA-10. These findings reveal a unique mechanism for the maintenance of appropriate levels of CED-1 to regulate apoptotic cell clearance.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Apoptose/fisiologia , Cadáver , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Fagocitose/fisiologia
20.
eNeuro ; 9(4)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35977825

RESUMO

Forgetting is important for animals to manage acquired memories to enable adaptation to changing environments; however, the neural network in mechanisms of forgetting is not fully understood. To understand the mechanisms underlying forgetting, we examined olfactory adaptation, a form of associative learning, in Caenorhabditis elegans The forgetting of diacetyl olfactory adaptation in C. elegans is regulated by secreted signals from AWC sensory neurons via the TIR-1/JNK-1 pathway. These signals cause a decline of the sensory memory trace in AWA neurons, where diacetyl is mainly sensed. To further understand the neural network that regulates this forgetting, we investigated the function of interneurons downstream of AWA and AWC neurons. We found that a pair of interneurons, AIA, is indispensable for the proper regulation of behavioral forgetting of diacetyl olfactory adaptation. Loss or inactivation of AIA caused the impairment of the chemotaxis recovery after adaptation without causing severe chemotaxis defects in the naive animal. AWA Ca2+ imaging analyses suggested that loss or inactivation of AIA interneurons did not affect the decline of the sensory memory trace after the recovery. Furthermore, AIA responses to diacetyl were observed in naive animals and after the recovery, but not just after the conditioning, suggesting that AIA responses after the recovery are required for the chemotaxis to diacetyl. We propose that the functional neuronal circuit for attractive chemotaxis to diacetyl is changed temporally at the recovery phase so that AIA interneurons are required for chemotaxis, although AIAs are dispensable for attractive chemotaxis to diacetyl in naive animals.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Quimiotaxia/fisiologia , Diacetil/metabolismo , Interneurônios/fisiologia , Células Receptoras Sensoriais/fisiologia
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