All Title Author
Keywords Abstract

PLOS Genetics  2008 

Sensory Perception of Food and Insulin-Like Signals Influence Seizure Susceptibility

DOI: 10.1371/journal.pgen.1000117

Full-Text   Cite this paper   Add to My Lib


Food deprivation is known to affect physiology and behavior. Changes that occur could be the result of the organism's monitoring of internal and external nutrient availability. In C. elegans, male mating is dependent on food availability; food-deprived males mate with lower efficiency compared to their well-fed counterparts, suggesting that the mating circuit is repressed in low-food environments. This behavioral response could be mediated by sensory neurons exposed to the environment or by internal metabolic cues. We demonstrated that food-deprivation negatively regulates sex-muscle excitability through the activity of chemosensory neurons and insulin-like signaling. Specifically, we found that the repressive effects of food deprivation on the mating circuit can be partially blocked by placing males on inedible food, E. coli that can be sensed but not eaten. We determined that the olfactory AWC neurons actively suppress sex-muscle excitability in response to food deprivation. In addition, we demonstrated that loss of insulin-like receptor (DAF-2) signaling in the sex muscles blocks the ability of food deprivation to suppress the mating circuit. During low-food conditions, we propose that increased activity by specific olfactory neurons (AWCs) leads to the release of neuroendocrine signals, including insulin-like ligands. Insulin-like receptor signaling in the sex muscles then reduces cell excitability via activation of downstream molecules, including PLC-γ and CaMKII.


[1]  LeBoeuf B, Gruninger TR, Garcia LR (2007) Food deprivation attenuates seizures through CaMKII and EAG K+ channels. PLoS Genet 3: 1622–1632.
[2]  Lakowski B, Hekimi S (1998) Survey of caloric restriction and aging in C. elegans. Proc Natl Acad Sci USA 95: 13091–13096.
[3]  Kaeberlein TL, Smith ED, Tsuchiya M, Welton KL, Thomas JH, et al. (2006) Lifespan extension in Caenorhabditis elegans by complete removal of food. Aging Cell 5: 487–494.
[4]  Lee GD, Wilson MA, Zhu M, Wolkow C, de Cabo R, et al. (2006) Dietary deprivation extends lifespan in Caenorhabditis elegans. Aging Cell 5: 515–524.
[5]  Bough KJ, Valiyil R, Han FT, Eagles DA (1999) Seizure resistance is dependent upon age and calorie restriction in rats fed a ketogenic diet. Epilepsy Res 35: 21–28.
[6]  Greene AE, Todorova MT, McGowan R, Seyfried TN (2001) Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose. Epilepsia 42: 1371–1378.
[7]  Mantis JG, Centeno NA, Todorova MT, McGowan R, Seyfried TN (2004) Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies. Nutr Metab (Lond) 1: 11.
[8]  Ward S, Carrel JS (1979) Fertilization and sperm competition in the nematode Caenorhabditis elegans. Dev Biol 73: 304–321.
[9]  Sulston JE, Albertson DG, Thomas JN (1980) The Caenorhabditis elegans male: postembryonic development of nongonadal structures. Developmental Biology 78: 542–576.
[10]  Loer CM, Kenyon CJ (1993) Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans. J Neurosci 13: 5407–5417.
[11]  Liu KS, Sternberg PW (1995) Sensory regulation of male mating behavior in Caenorhabditis elegans. Neuron 14: 79–89.
[12]  Garcia LR, Mehta P, Sternberg PW (2001) Regulation of distinct muscle behaviors controls the C. elegans male's copulatory spicules during mating. Cell 107: 777–788.
[13]  Gruninger TR, Gualberto DG, LeBoeuf B, Garcia LR (2006) Integration of male mating and feeding behaviors in Caenorhabditis elegans. J Neurosci 26: 169–179.
[14]  Garcia LR, Sternberg PW (2003) Caenorhabditis elegans UNC-103 ERG-like potassium channel regulates contractile behaviors of sex muscles in males before and during mating. J Neurosci 23: 2696–2705.
[15]  Nakai J, Ohkura M, Imoto K (2001) A high signal-to-noise Ca(2+) probe composed of a single green fluorescent protein. Nat Biotechnol 19: 137–141.
[16]  Reiner DJ, Weinshenker D, Tian H, Thomas JH, Nishiwaki K, et al. (2006) Behavioral genetics of Caenorhabditis elegans unc-103-encoded erg-like K(+) channel. J Neurogenet 20: 41–66.
[17]  Pisabarro AG, Prats R, Vaquez D, Rodriguez-Tebar A (1986) Activity of penicillin-binding protein 3 from Escherichia coli. J Bacteriol 168: 199–206.
[18]  Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, et al. (2003) Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421: 268–272.
[19]  Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, et al. (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425: 628–633.
[20]  Blacque OE, Reardon MJ, Li C, McCarthy J, Mahjoub MR, et al. (2004) Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev 18: 1630–1642.
[21]  Petersen CI, McFarland TR, Stepanovic SZ, Yang P, Reiner DJ, et al. (2004) In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia. Proc Natl Acad Sci U S A 101: 11773–11778.
[22]  Hodgkin J (1983) Male Phenotypes and Mating Efficiency in CAENORHABDITIS ELEGANS. Genetics 103: 43–64.
[23]  Park EC, Horvitz HR (1986) Mutations with dominant effects on the behavior and morphology of the nematode Caenorhabditis elegans. Genetics 113: 821–852.
[24]  Bargmann CI, Hartwieg E, Horvitz HR (1993) Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell 74: 515–527.
[25]  Colbert HA, Smith TL, Bargmann CI (1997) OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J Neurosci 17: 8259–8269.
[26]  Fukuyama M, Rougvie AE, Rothman JH (2006) C. elegans DAF-18/PTEN mediates nutrient-dependent arrest of cell cycle and growth in the germline. Curr Biol 16: 773–779.
[27]  Hong Y, Roy R, Ambros V (1998) Developmental regulation of a cyclin-dependent kinase inhibitor controls postembryonic cell cycle progression in Caenorhabditis elegans. Development 125: 3585–3597.
[28]  Munoz MJ, Riddle DL (2003) Positive selection of Caenorhabditis elegans mutants with increased stress resistance and longevity. Genetics 163: 171–180.
[29]  Bargmann CI (2006) Chemosensation in C. elegans. WormBook 1–29.
[30]  Cassada RC, Russell RL (1975) The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev Biol 46: 326–342.
[31]  Klass M, Hirsh D (1976) Non-ageing developmental variant of Caenorhabditis elegans. Nature 260: 523–525.
[32]  White JQ, Nicholas TJ, Gritton J, Truong L, Davidson ER, et al. (2007) The sensory circuitry for sexual attraction in C. elegans males. Curr Biol 17: 1847–1857.
[33]  Lipton J, Kleemann G, Ghosh R, Lints R, Emmons SW (2004) Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate. J Neurosci 24: 7427–7434.
[34]  Simon JM, Sternberg PW (2002) Evidence of a mate-finding cue in the hermaphrodite nematode Caenorhabditis elegans. Proc Natl Acad Sci U S A 99: 1598–1603.
[35]  Coburn CM, Bargmann CI (1996) A putative cyclic nucleotide-gated channel is required for sensory development and function in C. elegans. Neuron 17: 695–706.
[36]  Tobin D, Madsen D, Kahn-Kirby A, Peckol E, Moulder G, et al. (2002) Combinatorial expression of TRPV channel proteins defines their sensory functions and subcellular localization in C. elegans neurons. Neuron 35: 307–318.
[37]  Troemel ER, Kimmel BE, Bargmann CI (1997) Reprogramming chemotaxis responses: sensory neurons define olfactory preferences in C. elegans. Cell 91: 161–169.
[38]  Chalasani SH, Chronis N, Tsunozaki M, Gray JM, Ramot D, et al. (2007) Dissecting a circuit for olfactory behaviour in Caenorhabditis elegans. Nature 450: 63–70.
[39]  Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277: 942–946.
[40]  Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. 366: 461–464.
[41]  Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382: 536–539.
[42]  Albert PS, Riddle DL (1988) Mutants of Caenorhabditis elegans that form dauer-like larvae. Dev Biol 126: 270–293.
[43]  Van Voorhies WA, Ward S (1999) Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proc Natl Acad Sci U S A 96: 11399–11403.
[44]  Kodama E, Kuhara A, Mohri-Shiomi A, Kimura KD, Okumura M, et al. (2006) Insulin-like signaling and the neural circuit for integrative behavior in C. elegans. Genes Dev 20: 2955–2960.
[45]  Tomioka M, Adachi T, Suzuki H, Kunitomo H, Schafer WR, et al. (2006) The insulin/PI 3-kinase pathway regulates salt chemotaxis learning in Caenorhabditis elegans. Neuron 51: 613–625.
[46]  Murakami H, Bessinger K, Hellmann J, Murakami S (2005) Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans. J Neurosci 25: 10894–10904.
[47]  Saeki S, Yamamoto M, Iino Y (2001) Plasticity of chemotaxis revealed by paired presentation of a chemoattractant and starvation in the nematode Caenorhabditis elegans. J Exp Biol 204: 1757–1764.
[48]  Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G (1999) A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev 13: 1438–1452.
[49]  Larsen PL, Albert PS, Riddle DL (1995) Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139: 1567–1583.
[50]  Dorman JB, Albinder B, Shroyer T, Kenyon C (1995) The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141: 1399–1406.
[51]  Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, et al. (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389: 994–999.
[52]  Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: An HNF-3/forkhead Family Member That Can Function to Double the Life-Span of Caenorhabditis elegans 10.1126/science.278.5341.1319. Science 278: 1319–1322.
[53]  Vanfleteren JR, De Vreese A (1995) The gerontogenes age-1 and daf-2 determine metabolic rate potential in aging Caenorhabditis elegans. Faseb J 9: 1355–1361.
[54]  Wolkow CA, Kimura KD, Lee MS, Ruvkun G (2000) Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290: 147–150.
[55]  Gao L, Blair LA, Salinas GD, Needleman LA, Marshall J (2006) Insulin-like growth factor-1 modulation of CaV1.3 calcium channels depends on Ca2+ release from IP3-sensitive stores and calcium/calmodulin kinase II phosphorylation of the alpha1 subunit EF hand. Journal of Neuroscience 26: 6259–6268.
[56]  Blair LA, Bence-Hanulec KK, Mehta S, Franke T, Kaplan D, et al. (1999) Akt-dependent potentiation of L channels by insulin-like growth factor-1 is required for neuronal survival. Journal of Neuroscience 19: 1940–1951.
[57]  Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140: 823–833.
[58]  Van Buskirk C, Sternberg PW (2007) Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. Nat Neurosci 10: 1300–1307.
[59]  Gower NJ, Walker DS, Baylis HA (2005) Inositol 1,4,5-trisphosphate signaling regulates mating behavior in Caenorhabditis elegans males. Mol Biol Cell 16: 3978–3986.
[60]  Apfeld J, Kenyon C (1999) Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402: 804–809.
[61]  Alcedo J, Kenyon C (2004) Regulation of C. elegans longevity by specific gustatory and olfactory neurons.[see comment]. Neuron 41: 45–55.
[62]  Mak HY, Nelson LS, Basson M, Johnson CD, Ruvkun G (2006) Polygenic control of Caenorhabditis elegans fat storage. Nature Genetics 38: 363–368.
[63]  Bartness TJ, Bamshad M (1998) Innervation of mammalian white adipose tissue: implications for the regulation of total body fat. American Journal of Physiology 275: R1399–1411.
[64]  Ikeda A, Nishina PM, Naggert JK (2002) The tubby-like proteins, a family with roles in neuronal development and function. J Cell Sci 115: 9–14.
[65]  Katsanis N, Lupski JR, Beales PL (2001) Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10: 2293–2299.
[66]  Akman C, Zhao Q, Liu X, Holmes GL (2004) Effect of food deprivation during early development on cognition and neurogenesis in the rat. Epilepsy & Behavior 5: 446–454.
[67]  Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12: Suppl 21542–1552.
[68]  Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, et al. (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301: 1387–1391.
[69]  Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, et al. (1999) Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147: 435–446.
[70]  Huang WP, Scott SV, Kim J, Klionsky DJ (2000) The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem 275: 5845–5851.
[71]  Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J 19: 5720–5728.
[72]  Gray JM, Hill JJ, Bargmann CI (2005) A circuit for navigation in Caenorhabditis elegans. Proc Natl Acad Sci U S A 102: 3184–3191.
[73]  Stubdal H, Lynch CA, Moriarty A, Fang Q, Chickering T, et al. (2000) Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol Cell Biol 20: 878–882.
[74]  Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, et al. (1996) Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85: 281–290.
[75]  Noben-Trauth K, Naggert JK, North MA, Nishina PM (1996) A candidate gene for the mouse mutation tubby. Nature 380: 534–538.
[76]  Gems D, Riddle DL (2000) Genetic, behavioral and environmental determinants of male longevity in Caenorhabditis elegans. Genetics 154: 1597–1610.
[77]  Iser WB, Wolkow CA (2007) DAF-2/Insulin-Like Signaling in C. elegans Modifies Effects of Dietary Restriction and Nutrient Stress on Aging, Stress and Growth. PLoS ONE 2: e1240.
[78]  Li C (2005) The ever-expanding neuropeptide gene families in the nematode Caenorhabditis elegans. Parasitology 131: SupplS109–127.
[79]  Hodgkin J, Horvitz HR, Brenner S (1979) Nondisjunction mutants of the nematode Caenorhabditis elegans. Genetics 91: 67–94.
[80]  Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.
[81]  Swanson MM, Riddle DL (1981) Critical periods in the development of the Caenorhabditis elegans dauer larva. Dev Biol 84: 27–40.
[82]  Schnabel H, Schnabel R (1990) An organ-specific differentiation gene, pha-1, from Caenorhabditis elegans. Science 250: 686–688.
[83]  Colbert HA, Bargmann CI (1995) Odorant-specific adaptation pathways generate olfactory plasticity in C. elegans. Neuron 14: 803–812.
[84]  Reiner DJ, Thomas JH (1995) Reversal of a muscle response to GABA during C. elegans male development. J Neurosci 15: 6094–6102.
[85]  Husson SJ, Janssen T, Baggerman G, Bogert B, Kahn-Kirby AH, et al. (2007) Impaired processing of FLP and NLP peptides in carboxypeptidase E (EGL-21)-deficient Caenorhabditis elegans as analyzed by mass spectrometry. J Neurochem 102: 246–260.
[86]  Granato M, Schnabel H, Schnabel R (1994) pha-1, a selectable marker for gene transfer in C. elegans. Nucleic Acids Res 22: 1762–1763.
[87]  Bargmann CI, Avery L (1995) Laser killing of cells in Caenorhabditis elegans. In: Epstein HE, Shakes DC, editors. Caenorhabditis elegans: Modern Biological Analysis of an Organism. San Diego: Academic Press. pp. 225–250.


comments powered by Disqus