Energy Scarcity Promotes a Brain-wide Sleep State Modulated by Insulin Signaling in C. elegans

Abstract The progression of animal development from embryonic to juvenile life depends on the coordination of organism-wide responses with environmental conditions. We found that two transcription factors that function in interneuron differentiation in Caenorhabditis elegans, fax-1 and unc-42, are required for arousal and progression from embryogenesis to larval life by potentiating insulin signaling. The combination of mutations in either transcription factor and a mutation in daf-2 insulin receptor results in a novel peri-hatching arrest phenotype; embryos are fully-developed but inactive, often remaining trapped within the eggshell, and fail to initiate pharyngeal pumping. This pathway is opposed by an osmotic sensory response pathway that promotes developmental arrest and a sleep state at the end of embryogenesis in response to elevated salt concentration. The quiescent state induced by loss of insulin signaling or by osmotic stress can be reversed by mutations in genes that are required for sleep. Therefore, countervailing signals regulate late embryonic arousal and developmental progression to larval life, mechanistically linking the two responses. Our findings demonstrate a role for insulin signaling in an arousal circuit, consistent with evidence that insulin-related regulation may function in control of sleep states in many animals. The opposing quiescent arrest state may serve as an adaptive response to the osmotic threat from high salinity environments.

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Faculty Opinions recommendation of The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020955.240571 ◽

2004 ◽

Author(s):

Michael Hall

Keyword(s):

Life Span ◽

Larval Development ◽

Signaling Pathway ◽

Insulin Signaling ◽

Insulin Signaling Pathway ◽

Tor Pathway ◽

C Elegans

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Transcriptional targets of DAF-16 insulin signaling pathway protect C. elegans from extreme hypertonic stress

AJP Cell Physiology ◽

10.1152/ajpcell.00451.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. C467-C474 ◽

Cited By ~ 91

Author(s):

S. Todd Lamitina ◽

Kevin Strange

Keyword(s):

Insulin Signaling ◽

Stress Resistance ◽

Molecular Mechanisms ◽

Organic Osmolytes ◽

Dependent Manner ◽

Animal Cells ◽

Hypertonic Stress ◽

C Elegans ◽

Downstream Target ◽

Molecular Damage

All cells adapt to hypertonic stress by regulating their volume after shrinkage, by accumulating organic osmolytes, and by activating mechanisms that protect against and repair hypertonicity-induced damage. In mammals and nematodes, inhibition of signaling from the DAF-2/IGF-1 insulin receptor activates the DAF-16/FOXO transcription factor, resulting in increased life span and resistance to some types of stress. We tested the hypothesis that inhibition of insulin signaling in Caenorhabditis elegans also increases hypertonic stress resistance. Genetic inhibition of DAF-2 or its downstream target, the AGE-1 phosphatidylinositol 3-kinase, confers striking resistance to a normally lethal hypertonic shock in a DAF-16-dependent manner. However, insulin signaling is not inhibited by or required for adaptation to hypertonic conditions. Microarray studies have identified 263 genes that are transcriptionally upregulated by DAF-16 activation. We identified 14 DAF-16-upregulated genes by RNA interference screening that are required for age- 1 hypertonic stress resistance. These genes encode heat shock proteins, proteins of unknown function, and trehalose synthesis enzymes. Trehalose levels were elevated approximately twofold in age- 1 mutants, but this increase was insufficient to prevent rapid hypertonic shrinkage. However, age- 1 animals unable to synthesize trehalose survive poorly under hypertonic conditions. We conclude that increased expression of proteins that protect eukaryotic cells against environmental stress and/or repair stress-induced molecular damage confers hypertonic stress resistance in C. elegans daf- 2/ age- 1 mutants. Elevated levels of solutes such as trehalose may also function in a cytoprotective manner. Our studies provide novel insights into stress resistance in animal cells and a foundation for new studies aimed at defining molecular mechanisms underlying these essential processes.

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Fractal scaling of C. elegans behavior is shaped by insulin signaling

10.21203/rs.3.rs-1136340/v1 ◽

2021 ◽

Author(s):

Yukinobu Arata ◽

Itsuki Shiga ◽

Yusaku Ikeda ◽

Hiroshi Kimura ◽

Peter Jurica ◽

...

Keyword(s):

Residence Time ◽

Insulin Signaling ◽

Time Distribution ◽

Animal Species ◽

Power Law Distribution ◽

Fractal Scaling ◽

C Elegans ◽

Fractal Analyses ◽

Patients With Diabetes ◽

Behavioral Activities

Abstract Fractal scaling governs the complex behavior of various animal species and, in humans, can be altered by neurodegenerative diseases and aging1. However, the mechanism underlying fractal scaling remains unknown. Here, we videorecorded C. elegans that had been cultured in a microfluidic device for 3 days and analyzed temporal patterns of C. elegans actions by fractal analyses. The residence-time distribution of C. elegans shared a common feature with those of human and mice2–4. Specifically, the residence-time power-law distribution of the active state changed to an exponential-like decline at a longer time scale, whereas this change did not occur in the inactive state. The exponential-like decline disappeared in starved C. elegans but was restored by culturing animals with glucose. The exponential-like decline similarly disappeared in insulin-signaling daf-2 and daf-16 mutants. Therefore, we conclude that insulin signaling regulates fractal scaling of C. elegans behavior. Our findings indicate that neurosensory modulation of C. elegans behavior by insulin signaling is achieved by regulation of fractal scaling. In humans, diabetes mellitus is associated with depression, bipolar disorder, and anxiety disorder5, which affect daily behavioral activities. We hypothesize that comorbid behavioral defects in patients with diabetes may be attributed to altered fractal scaling of human behavior.

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A quiescent state following mild sensory arousal in Caenorhabditis elegans is potentiated by stress

10.1101/784306 ◽

2019 ◽

Author(s):

Patrick D. McClanahan ◽

Jessica M. Dubuque ◽

Daphne Kontogiorgos-Heintz ◽

Ben F. Habermeyer ◽

Joyce H. Xu ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Light Exposure ◽

Light Stimulus ◽

Low Frequency ◽

Behavioral Responses ◽

Quiescent State ◽

Sleep State ◽

C Elegans ◽

Epidermal Growth ◽

Cellular Stressors

AbstractAn animal’s behavioral and physiological response to stressors includes changes to its responses to stimuli. How such changes occur is not well understood. Here we describe a Caenorhabditis elegans quiescent behavior, post-response quiescence (PRQ), which is modulated by the C. elegans response to cellular stressors. Following an aversive mechanical or blue light stimulus, worms respond first by briefly moving, and then become more quiescent for a period lasting tens of seconds. PRQ occurs at low frequency in unstressed animals, but is more frequent in animals that have experienced cellular stress due to ultraviolet light exposure as well as in animals following overexpression of epidermal growth factor (EGF). PRQ requires the function of the carboxypeptidase EGL-21 and the calcium-activated protein for secretion (CAPS) UNC-31, suggesting it has a neuropeptidergic mechanism. Although PRQ requires the sleep-promoting neurons RIS and ALA, it is not accompanied by decreased arousability, and does not appear to be homeostatically regulated, suggesting that it is not a sleep state. PRQ represents a simple, tractable model for studying how neuromodulatory states like stress alter behavioral responses to stimuli.

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Modulatory upregulation of an insulin peptide gene by different pathogens in C. elegans

10.1101/238568 ◽

2017 ◽

Author(s):

Song-Hua Lee ◽

Shizue Omi ◽

Nishant Thakur ◽

Clara Taffoni ◽

Jérôme Belougne ◽

...

Keyword(s):

Gene Expression ◽

Insulin Signaling ◽

Kinase Inhibitor ◽

Innate Immune ◽

Immune Genes ◽

C Elegans ◽

Intestinal Infections ◽

Innate Immune Genes ◽

Peptide Gene ◽

Complex Manner

ABSTRACTWhen an animal is infected, its innate immune response needs to be tightly regulated across tissues and coordinated with other aspects of organismal physiology. Previous studies with Caenorhabditis elegans have demonstrated that insulin-like peptide genes are differentially expressed in response to different pathogens. They represent prime candidates for conveying signals between tissues upon infection. Here, we focused on one such gene, ins-11 and its potential role in mediating cross-tissue regulation of innate immune genes. While diverse bacterial intestinal infections can trigger the up-regulation of ins-11 in the intestine, we show that epidermal infection with the fungus Drechmeria coniospora triggers an upregulation of ins-11 in the epidermis. Using the Shigella virulence factor OpsF, a MAP kinase inhibitor, we found that in both cases, ins-11 expression is controlled cell autonomously by p38 MAPK, but via distinct transcription factors, STA-2/STAT in the epidermis and HLH-30/TFEB in the intestine. We established that ins-11, and the insulin signaling pathway more generally, are not involved in the regulation of antimicrobial peptide gene expression in the epidermis. The up-regulation of ins-11 in the epidermis does, however, affect intestinal gene expression in a complex manner, and has a deleterious effect on longevity. These results support a model in which insulin signaling, via ins-11, contributes to the coordination of the organismal response to infection, influencing the allocation of resources in an infected animal.

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Decoy receptor fine tunes insulin signaling in C. elegans

Lab Animal ◽

10.1038/s41684-020-0513-5 ◽

2020 ◽

Vol 49 (4) ◽

pp. 112-112

Author(s):

Alexandra Le Bras

Keyword(s):

Insulin Signaling ◽

Decoy Receptor ◽

C Elegans

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DAF-16 and SMK-1 Contribute to Innate Immunity During Adulthood in Caenorhabditis elegans

G3 Genes|Genome|Genetics ◽

10.1534/g3.120.401166 ◽

2020 ◽

Vol 10 (5) ◽

pp. 1521-1539 ◽

Cited By ~ 1

Author(s):

Daniel R. McHugh ◽

Elena Koumis ◽

Paul Jacob ◽

Jennifer Goldfarb ◽

Michelle Schlaubitz-Garcia ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Caenorhabditis Elegans ◽

Host Defense ◽

Insulin Signaling ◽

Bacterial Pathogens ◽

C Elegans ◽

Link Type ◽

Age Dependent ◽

Over Time

Aging is accompanied by a progressive decline in immune function termed “immunosenescence”. Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm Caenorhabditis elegans levels of PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in C. elegans is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger C. elegansDAF-16 is inactive unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of C. elegans (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

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Identification of ATF-7 and the insulin signaling pathway in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen species

PLoS ONE ◽

10.1371/journal.pone.0177432 ◽

2017 ◽

Vol 12 (6) ◽

pp. e0177432 ◽

Cited By ~ 6

Author(s):

Julie A. Hall ◽

Matthew K. McElwee ◽

Jonathan H. Freedman

Keyword(s):

Reactive Oxygen Species ◽

Signaling Pathway ◽

Insulin Signaling ◽

Reactive Oxygen ◽

Insulin Signaling Pathway ◽

Oxygen Species ◽

C Elegans

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Electrophysiological Measures of Aging Pharynx Function in C. elegans Reveal Enhanced Organ Functionality in Older, Long-lived Mutants

The Journals of Gerontology Series A ◽

10.1093/gerona/glx230 ◽

2017 ◽

Vol 74 (8) ◽

pp. 1173-1179 ◽

Cited By ~ 7

Author(s):

Joshua Coulter Russell ◽

Nikolay Burnaevskiy ◽

Bridget Ma ◽

Miguel Arenas Mailig ◽

Franklin Faust ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Heat Shock ◽

Life Span ◽

Insulin Signaling ◽

Model System ◽

Wild Type ◽

Organ Function ◽

C Elegans ◽

Age Related ◽

The Relationship

Abstract The function of the pharynx, an organ in the model system Caenorhabditis elegans, has been correlated with life span and motility (another measure of health) since 1980. In this study, in order to further understand the relationship between organ function and life span, we measured the age-related decline of the pharynx using an electrophysiological approach. We measured and analyzed electropharyngeograms (EPG) of wild type animals, short-lived hsf-1 mutants, and long-lived animals with genetically decreased insulin signaling or increased heat shock pathway signaling; we recorded a total of 2,478 EPGs from 1,374 individuals. As expected, the long-lived daf-2(e1370) and hsf-1OE(uthIs235) animals maintained pharynx function relatively closer to the youthful state during aging, whereas the hsf-1(sy441) and wild type animals’ pharynx function deviated significantly further from the youthful state at advanced age. Measures of the amount of variation in organ function can act as biomarkers of youthful physiology as well. Intriguingly, the long-lived animals had greater variation in the duration of pharynx contraction at older ages.

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