scholarly journals Toxic stress-specific cytoprotective responses regulate learned behavioral decisions in C. elegans

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gábor Hajdú ◽  
Eszter Gecse ◽  
István Taisz ◽  
István Móra ◽  
Csaba Sőti
Keyword(s):  
Stress Responses ◽  
Cross Tolerance ◽  
Food Avoidance ◽  
C Elegans ◽  
Behavioral Decision ◽  
Regulatory Link ◽  
High Concentrations ◽  
Aversive Behavior ◽  
Behavioral Defenses ◽  
Fight Or Flight

Abstract Background Recognition of stress and mobilization of adequate “fight-or-flight” responses is key for survival and health. Previous studies have shown that exposure of Caenorhabditis elegans to pathogens or toxins simultaneously stimulates cellular stress and detoxification responses and aversive behavior. However, whether a coordinated regulation exists between cytoprotective stress responses and behavioral defenses remains unclear. Results Here, we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and food avoidance behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf2, and Hsp90 in non-neuronal cells, which confer both physiological (increased survival) and behavioral tolerance (reduced food avoidance) to benzaldehyde exposure. Benzaldehyde preconditioning also elicits behavioral cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance, weakens physiological diacetyl tolerance, and does not induce apparent molecular defenses. The inter-tissue connection between cellular and behavioral defenses is mediated by JNK-like stress-activated protein kinases and the neuropeptide Y receptor NPR-1. Reinforcement of the stressful experiences using spaced training forms stable stress-specific memories. Memory retrieval by the olfactory cues leads to avoidance of food contaminated by diacetyl and context-dependent behavioral decision to avoid benzaldehyde only if there is an alternative, food-indicative odor. Conclusions Our study reveals a regulatory link between conserved cytoprotective stress responses and behavioral avoidance, which underlies “fight-or-flight” responses and facilitates self-protection in real and anticipated stresses. These findings imply that variations in the efficiency of physiological protection during past episodes of stress might shape current behavioral decisions. Graphical abstract

scholarly journals Toxic stress-specific cytoprotective responses regulate learned behavioral decisions in C. elegans

2020 ◽  
Author(s):  
Gábor Hajdú ◽  
Eszter Gecse ◽  
István Taisz ◽  
István Móra ◽  
Csaba Sőti
Keyword(s):  
Stress Responses ◽  
Physiological Stress ◽  
Cross Tolerance ◽  
Coordinate Regulation ◽  
C Elegans ◽  
Behavioral Decision ◽  
Regulatory Link ◽  
High Concentrations ◽  
Aversive Behavior ◽  
Self Protection

AbstractBackgroundProtection of organismal integrity involve physiological stress responses and behavioral defenses. Recent studies in the roundworm Caenorhabditis elegans have shown that pathogen and toxin exposure simultaneously stimulate cellular stress and detoxification responses and aversive behavior. However, whether a coordinate regulation exists between cellular and neurobehavioral defenses remains unclear.ResultsHere we show that exposure of C. elegans to high concentrations of naturally attractive food-derived odors, benzaldehyde and diacetyl, induces toxicity and aversive behavior. Benzaldehyde preconditioning activates systemic cytoprotective stress responses involving DAF-16/FOXO, SKN-1/Nrf and Hsp90 in somatic cells, which confer behavioral tolerance to benzaldehyde and cross-tolerance to the structurally similar methyl-salicylate, but not to the structurally unrelated diacetyl. In contrast, diacetyl preconditioning augments diacetyl avoidance and does not induce apparent molecular defenses. Reinforcement of the experiences using massed training forms relevant associative memories. Memory retrieval by the odor olfactory cues leads to avoidance of food contaminated by diacetyl and context-dependent behavioral decision to avoid benzaldehyde only if there is an alternative, food-indicative odor.ConclusionsOur findings reveal a regulatory link between physiological stress responses and learned behavior which facilitates self-protection in real and anticipated stresses. The potential conservation of this somato-neuronal connection might have relevance in maladaptive avoidant human behaviors.

scholarly journals Acute-stress impairs cytoprotective mechanisms through neural inhibition of the insulin pathway

2018 ◽  
Author(s):  
Maria José De Rosa ◽  
Tania Veuthey ◽  
Jeremy Florman ◽  
Jeff Grant ◽  
Gabriela Blanco ◽  
...  
Keyword(s):  
Stress Responses ◽  
Nuclear Translocation ◽  
Acute Stress ◽  
Flight Response ◽  
C Elegans ◽  
State Dependent ◽  
Neural Inhibition ◽  
Fight Or Flight Response ◽  
Fight Or Flight

ABSTRACTPersistent activation of the “fight-or-flight” response accelerates aging and increases the susceptibility to disease. We show that repeated induction of the C. elegans flight response inhibits conserved cytoprotective mechanisms. This acute-stress response activates neurons that release tyramine, the invertebrate analog of adrenaline/noradrenaline. Tyramine stimulates the DAF-2/Insulin/IGF-1 pathway and precludes the nuclear translocation of the DAF-16/FOXO transcription factor through the activation of an adrenergic-like receptor TYRA-3 in the intestine. In contrast, environmental long-term stressors, such as heat or oxidative stress, reduce tyramine release allowing the induction of FOXO-dependent cytoprotective genes. These findings demonstrate how a neural stress-hormone signaling provides a state-dependent neural switch between acute and long-term stress responses, and provide mechanistic insights how acute stress impairs cellular defensive systems.One Sentence Summary: The “fight-or-flight” response reduces resistance to environmental challenges.

Antifungal Activity Directed Toward the Cell Wall by 2-Cyclohexylidenhydrazo- 4-Phenyl-Thiazole Against Candida albicans

2019 ◽  
Vol 19 (4) ◽  
pp. 428-438 ◽  
Author(s):  
Nívea P. de Sá ◽  
Ana P. Pôssa ◽  
Pilar Perez ◽  
Jaqueline M.S. Ferreira ◽  
Nayara C. Fonseca ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Mammalian Cells ◽  
C Elegans ◽  
Buccal Epithelial Cells ◽  
Mutant Strains ◽  
Low Toxicity ◽  
High Concentrations ◽  
Mic Value

<p>Background: The increasing incidence of invasive forms of candidiasis and resistance to antifungal therapy leads us to seek new and more effective antifungal compounds. </P><P> Objective: To investigate the antifungal activity and toxicity as well as to evaluate the potential targets of 2- cyclohexylidenhydrazo-4-phenyl-thiazole (CPT) in Candida albicans. </P><P> Methods: The antifungal activity of CPT against the survival of C. albicans was investigated in Caenorhabditis elegans. Additionally, we determined the effect of CPT on the inhibition of C. albicans adhesion capacity to buccal epithelial cells (BECs), the toxicity of CPT in mammalian cells, and the potential targets of CPT in C. albicans. </P><P> Results: CPT exhibited a minimum inhibitory concentration (MIC) value of 0.4-1.9 µg/mL. Furthermore, CPT at high concentrations (>60 x MIC) showed no or low toxicity in HepG2 cells and <1% haemolysis in human erythrocytes. In addition, CPT decreased the adhesion capacity of yeasts to the BECs and prolonged the survival of C. elegans infected with C. albicans. Analysis of CPT-treated cells showed that their cell wall was thinner than that of untreated cells, especially the glucan layer. We found that there was a significantly lower quantity of 1,3-β-D-glucan present in CPT-treated cells than that in untreated cells. Assays performed on several mutant strains showed that the MIC value of CPT was high for its antifungal activity on yeasts with defective 1,3-β-glucan synthase. </P><P> Conclusion: In conclusion, CPT appears to target the cell wall of C. albicans, exhibits low toxicity in mammalian cells, and prolongs the survival of C. elegans infected with C. albicans.</p>

The Caenorhabditis elegans odr-2 Gene Encodes a Novel Ly-6-Related Protein Required for Olfaction

Genetics ◽  
2001 ◽  
Vol 157 (1) ◽  
pp. 211-224 ◽  
Author(s):  
Joseph H Chou ◽  
Cornelia I Bargmann ◽  
Piali Sengupta
Keyword(s):  
Caenorhabditis Elegans ◽  
Motor Neurons ◽  
Amino Terminus ◽  
Signaling Proteins ◽  
Related Protein ◽  
Olfactory Neurons ◽  
Unique Role ◽  
C Elegans ◽  
Founding Member ◽  
High Concentrations

Abstract Caenorhabditis elegans odr-2 mutants are defective in the ability to chemotax to odorants that are recognized by the two AWC olfactory neurons. Like many other olfactory mutants, they retain responses to high concentrations of AWC-sensed odors; we show here that these residual responses are caused by the ability of other olfactory neurons (the AWA neurons) to be recruited at high odor concentrations. odr-2 encodes a membrane-associated protein related to the Ly-6 superfamily of GPI-linked signaling proteins and is the founding member of a C. elegans gene family with at least seven other members. Alternative splicing of odr-2 yields three predicted proteins that differ only at the extreme amino terminus. The three isoforms have different promoters, and one isoform may have a unique role in olfaction. An epitope-tagged ODR-2 protein is expressed at high levels in sensory neurons, motor neurons, and interneurons and is enriched in axons. The AWC neurons are superficially normal in their development and structure in odr-2 mutants, but their function is impaired. Our results suggest that ODR-2 may regulate AWC signaling within the neuronal network required for chemotaxis.

Rubidium chloride increases lifespan through an AMPK/FOXO-dependent pathway in Caenorhabditis elegans

2021 ◽  
Author(s):  
Mengjiao Hao ◽  
Zhikang Zhang ◽  
Yijun Guo ◽  
Huihao Zhou ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Aging Effect ◽  
Stress Effect ◽  
Neuroprotective Effects ◽  
C Elegans ◽  
Cycle Arrest ◽  
Age Related ◽  
Promising Target ◽  
Amp Activated Protein Kinase

Abstract AMP-activated protein kinase (AMPK) is involved in life span maintenance, stress responses, and germ cell cycle arrest upon dauer entry. AMPK is currently considered a promising target for preventing age-related diseases. Rubidium is one of the trace elements in human body. As early as the 1970s, RbCl has been was reported to have neuroprotective effects. In this work, we report the anti-aging effect of RbCl in Caenorhabditis elegans. Specifically, we reveal that (1) RbCl does increase the lifespan and enhance stress resistance in C. elegans without disturbing their fecundity. (2) RbCl induces superoxide dismutase (SOD) expression, which is essential for its anti-aging and anti-stress effect. (3) AAK-2 and DAF-16 are essential to the anti-aging efficacy of RbCl, and RbCl can promote DAF-16 translocating into the nucleus, suggesting that RbCl delays aging through regulating AMPK/FOXO pathway. RbCl can be a promising agent against aging related diseases.

scholarly journals In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria

2020 ◽  
Vol 21 (21) ◽  
pp. 7813
Author(s):  
Kiho Lee ◽  
Iliana Escobar ◽  
Yeeun Jang ◽  
Wooseong Kim ◽  
Frederick M. Ausubel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Kinase Gene ◽  
Concentration Dependent Manner ◽  
C Elegans ◽  
Opportunistic Bacteria ◽  
Free Living Nematode

Sphingosine-1-phophate (S1P) is a sphingolipid-derived signaling molecule that controls diverse cellular functions including cell growth, homeostasis, and stress responses. In a variety of metazoans, cytosolic S1P is transported into the extracellular space where it activates S1P receptors in a concentration-dependent manner. In the free-living nematode Caenorhabditis elegans, the spin-2 gene, which encodes a S1P transporter, is activated during Gram-positive or Gram-negative bacterial infection of the intestine. However, the role during infection of spin-2 and three additional genes in the C. elegans genome encoding other putative S1P transporters has not been elucidated. Here, we report an evolutionally conserved function for S1P and a non-canonical role for S1P transporters in the C. elegans immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene (sphk-1) or in the S1P transporter genes spin-2 or spin-3 decreased nematode survival after infection with Pseudomonas aeruginosa or Enterococcus faecalis. In contrast to spin-2 and spin-3, mutating spin-1 leads to an increase in resistance to P. aeruginosa. Consistent with these results, when wild-type C. elegans were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with P. aeruginosa and E. faecalis. In comparison, spin-2 and spin-3 mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the spin-1 mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward P. aeruginosa and Escherichia coli and only minimal activity against E. faecalis MMH594 (40 µM). These data suggest that spin-2 and spin-3, on the one hand, and spin-1, on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in C. eleganssek-1 and pmk-1 mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.

scholarly journals New Antimicrobial Bioactivity against Multidrug-Resistant Gram-Positive Bacteria of Kinase Inhibitor IMD0354

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 665
Author(s):  
Iliana E Escobar ◽  
Alexis White ◽  
Wooseong Kim ◽  
Eleftherios Mylonakis
Keyword(s):  
Staphylococcus Aureus ◽  
Kinase Inhibitor ◽  
Cell Attachment ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
C Elegans ◽  
Vancomycin Resistant ◽  
High Concentrations

Multidrug-resistant pathogens pose a serious threat to human health. For decades, the antibiotic vancomycin has been a potent option when treating Gram-positive multidrug-resistant infections. Nonetheless, in recent decades, we have begun to see an increase in vancomycin-resistant bacteria. Here, we show that the nuclear factor-kappa B (NF-κB) inhibitor N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a Caenorhabditis elegans–methicillin-resistant Staphylococcus aureus (MRSA) infection screen. IMD0354 was a potent bacteriostatic drug capable of working at a minimal inhibitory concentration (MIC) as low as 0.06 µg/mL against various vancomycin-resistant strains. Interestingly, IMD0354 showed no hemolytic activity at concentrations as high as 16 µg/mL and is minimally toxic to C. elegans in vivo with 90% survival up to 64 µg/mL. In addition, we demonstrated that IMD0354′s mechanism of action at high concentrations is membrane permeabilization. Lastly, we found that IMD0354 is able to inhibit vancomycin-resistant Staphylococcus aureus (VRSA) initial cell attachment and biofilm formation at sub-MIC levels and above. Our work highlights that the NF-κB inhibitor IMD0354 has promising potential as a lead compound and an antimicrobial therapeutic candidate capable of combating multidrug-resistant bacteria.

Characterization of the xenobiotic response of Caenorhabditis elegans to the anthelmintic drug albendazole and the identification of novel drug glucoside metabolites

2010 ◽  
Vol 432 (3) ◽  
pp. 505-516 ◽  
Author(s):  
Steven T. Laing ◽  
Al Ivens ◽  
Roz Laing ◽  
Sai Ravikumar ◽  
Victoria Butler ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Metabolizing Enzymes ◽  
C Elegans ◽  
Genes Encoding ◽  
Minimal Importance ◽  
Xenobiotic Response ◽  
Novel Drug ◽  
Anthelmintic Drugs

Knowledge of how anthelmintics are metabolized and excreted in nematodes is an integral part of understanding the factors that determine their potency, spectrum of activity and for investigating mechanisms of resistance. Although there is remarkably little information on these processes in nematodes, it is often suggested that they are of minimal importance for the major anthelmintic drugs. Consequently, we have investigated how the model nematode Caenorhabditis elegans responds to and metabolizes albendazole, one of the most important anthelmintic drugs for human and animal use. Using a mutant strain lacking the β-tubulin drug target to minimize generalized stress responses, we show that the transcriptional response is dominated by genes encoding XMEs (xenobiotic-metabolizing enzymes), particularly cytochrome P450s and UGTs (UDP-glucuronosyl transferases). The most highly induced genes are predominantly expressed in the worm intestine, supporting their role in drug metabolism. HPLC-MS/MS revealed the production of two novel glucoside metabolites in C. elegans identifying a major difference in the biotransformation of this drug between nematodes and mammals. This is the first demonstration of metabolism of a therapeutic anthelmintic in C. elegans and provides a framework for its use to functionally investigate nematode anthelmintic metabolism.

scholarly journals Aversive Behavior in the Nematode C. elegans Is Modulated by cGMP and a Neuronal Gap Junction Network

PLoS Genetics ◽  
2016 ◽  
Vol 12 (7) ◽  
pp. e1006153 ◽  
Author(s):  
Michelle C. Krzyzanowski ◽  
Sarah Woldemariam ◽  
Jordan F. Wood ◽  
Aditi H. Chaubey ◽  
Chantal Brueggemann ◽  
...  
Keyword(s):  
Gap Junction ◽  
C Elegans ◽  
Aversive Behavior

scholarly journals A collective modulatory basis for multisensory integration in C. elegans

2018 ◽  
Author(s):  
Gareth Harris ◽  
Taihong Wu ◽  
Gaia Linfield ◽  
Myung-Kyu Choi ◽  
He Liu ◽  
...  
Keyword(s):  
Decision Making ◽  
Nervous System ◽  
Multisensory Integration ◽  
Multisensory Processing ◽  
Neurological Diseases ◽  
Sensory Information ◽  
Sensory Cues ◽  
C Elegans ◽  
Behavioral Decision ◽  
Integrated Response

AbstractIn the natural environment, animals often encounter multiple sensory cues that are simultaneously present. The nervous system integrates the relevant sensory information to generate behavioral responses that have adaptive values. However, the signal transduction pathways and the molecules that regulate integrated behavioral response to multiple sensory cues are not well defined. Here, we characterize a collective modulatory basis for a behavioral decision in C. elegans when the animal is presented with an attractive food source together with a repulsive odorant. We show that distributed neuronal components in the worm nervous system and several neuromodulators orchestrate the decision-making process, suggesting that various states and contexts may modulate the multisensory integration. Among these modulators, we identify a new function of a conserved TGF-β pathway that regulates the integrated decision by inhibiting the signaling from a set of central neurons. Interestingly, we find that a common set of modulators, including the TGF-β pathway, regulate the integrated response to the pairing of different foods and repellents. Together, our results provide insights into the modulatory signals regulating multisensory integration and reveal potential mechanistic basis for the complex pathology underlying defects in multisensory processing shared by common neurological diseases.Author SummaryThe present study characterizes the modulation of a behavioral decision in C. elegans when the worm is presented with a food lawn that is paired with a repulsive smell. We show that multiple sensory neurons and interneurons play roles in making the decision. We also identify several modulatory molecules that are essential for the integrated decision when the animal faces a choice between the cues of opposing valence. We further show that many of these factors, which often represent different states and contexts, are common for behavioral decisions that integrate sensory information from different types of foods and repellents. Overall, our results reveal a collective molecular and cellular basis for integration of simultaneously present attractive and repulsive cues to fine-tune decision-making.

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