Insulin signaling represents a gating mechanism between different memory phases in Drosophila larvae

Autoři: Melanie Eschment aff001;  Hanna R. Franz aff002;  Nazlı Güllü aff001;  Luis G. Hölscher aff002;  Ko-Eun Huh aff002;  Annekathrin Widmann aff001
Působiště autorů: Department of Biology, University of Konstanz, Konstanz, Germany aff001;  Department of Molecular Neurobiology of Behavior, University of Göttingen, Göttingen, Germany aff002
Vyšlo v časopise: Insulin signaling represents a gating mechanism between different memory phases in Drosophila larvae. PLoS Genet 16(10): e32767. doi:10.1371/journal.pgen.1009064
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009064


The ability to learn new skills and to store them as memory entities is one of the most impressive features of higher evolved organisms. However, not all memories are created equal; some are short-lived forms, and some are longer lasting. Formation of the latter is energetically costly and by the reason of restricted availability of food or fluctuations in energy expanses, efficient metabolic homeostasis modulating different needs like survival, growth, reproduction, or investment in longer lasting memories is crucial. Whilst equipped with cellular and molecular pre-requisites for formation of a protein synthesis dependent long-term memory (LTM), its existence in the larval stage of Drosophila remains elusive. Considering it from the viewpoint that larval brain structures are completely rebuilt during metamorphosis, and that this process depends completely on accumulated energy stores formed during the larval stage, investing in LTM represents an unnecessary expenditure. However, as an alternative, Drosophila larvae are equipped with the capacity to form a protein synthesis independent so-called larval anaesthesia resistant memory (lARM), which is consolidated in terms of being insensitive to cold-shock treatments. Motivated by the fact that LTM formation causes an increase in energy uptake in Drosophila adults, we tested the idea of whether an energy surplus can induce the formation of LTM in the larval stage. Suprisingly, increasing the metabolic state by feeding Drosophila larvae the disaccharide sucrose directly before aversive olfactory conditioning led to the formation of a protein synthesis dependent longer lasting memory. Moreover, formation of this memory component is accompanied by the suppression of lARM. We ascertained that insulin receptors (InRs) expressed in the mushroom body Kenyon cells suppresses the formation of lARM and induces the formation of a protein synthesis dependent longer lasting memory in Drosophila larvae. Given the numerical simplicity of the larval nervous system this work offers a unique prospect to study the impact of insulin signaling on the formation of protein synthesis dependent memories on a molecular level.

Klíčová slova:

Drosophila melanogaster – Insulin – Insulin signaling – Larvae – Memory – Protein synthesis – Sensory perception – Sucrose


1. Kandel ER, Dudai Y, Mayford MR. The molecular and systems biology of memory. Cell. 2014;157: 163–186. doi: 10.1016/j.cell.2014.03.001 24679534

2. Dukas R. Costs of memory: Ideas and predictions. J Theor Biol. 1999. doi: 10.1006/jtbi.1998.0856 10036206

3. Johnston TD. Selective Costs and Benefits in the Evolution of Learning. Adv Study Behav. 1982. doi: 10.1016/S0065-3454(08)60046-7

4. Burns JG, Foucaud J, Mery F. Costs of memory: Lessons from “mini” brains. Proceedings of the Royal Society B: Biological Sciences. 2011. doi: 10.1098/rspb.2010.2488 21177679

5. Dunlap AS, Stephens DW. Components of change in the evolution of learning and unlearned preference. Proc R Soc B Biol Sci. 2009. doi: 10.1098/rspb.2009.0602 19535373

6. Burger JMS, Kolss M, Pont J, Kawecki TJ. Learning ability and longevity: A symmetrical evolutionary trade-off in Drosophila. Evolution (N Y). 2008;62: 1294–304. doi: 10.1111/j.1558-5646.2008.00376.x 18363867

7. Mery F, Kawecki TJ. A fitness cost of learning ability in Drosophila melanogaster. Proc R Soc B Biol Sci. 2003;270: 2465–9. doi: 10.1098/rspb.2003.2548 14667336

8. Lagasse F, Moreno C, Preat T, Mery F. Functional and evolutionary trade-offs co-occur between two consolidated memory phases in Drosophila melanogaster. Proc R Soc B Biol Sci. 2012;279: 4015–23. doi: 10.1098/rspb.2012.1457 22859595

9. Evans Lisa J, Smith Karen E, Raine NE. Fast learning in free-foraging bumble bees is negatively correlated with lifetime resource collection. Sci Rep. 2017. doi: 10.1038/s41598-017-00389-0 28356567

10. Christiansen IC, Szin S, Schausberger P. Benefit-cost Trade-offs of Early Learning in Foraging Predatory Mites Amblyseius Swirskii. Sci Rep. 2016. doi: 10.1038/srep23571 27006149

11. Kotrschal A, Rogell B, Bundsen A, Svensson B, Zajitschek S, Brännström I, et al. Artificial selection on relative brain size in the guppy reveals costs and benefits of evolving a larger brain. Curr Biol. 2013. doi: 10.1016/j.cub.2012.11.058 23290552

12. Snell-Rood EC, Davidowitz G, Papaj DR. Reproductive tradeoffs of learning in a butterfly. Behav Ecol. 2011. doi: 10.1093/beheco/arq169

13. Jaumann S, Scudelari R, Naug D. Energetic cost of learning and memory can cause cognitive impairment in honeybees. Biol Lett. 2013. doi: 10.1098/rsbl.2013.0149 23784929

14. Mery F, Kawecki TJ. A cost of long-term memory in Drosophila. Science. 2005. doi: 10.1126/science.1111331 15905396

15. Placais PY, Preat T, Disables B. To favor survival under food shortage, the brain disables costly memory. Science. 2013;339: 440–442. doi: 10.1126/science.1226018 23349289

16. McGuire SE, Deshazer M, Davis RL. Thirty years of olfactory learning and memory research in Drosophila melanogaster. Prog Neurobiol. 2005;76: 328–347. doi: 10.1016/j.pneurobio.2005.09.003 16266778

17. Bouzaiane E, Trannoy S, Scheunemann L, Plaçais PY, Preat T. Two Independent Mushroom Body Output Circuits Retrieve the Six Discrete Components of Drosophila Aversive Memory. Cell Rep. 2015;11: 1280–1292. doi: 10.1016/j.celrep.2015.04.044 25981036

18. Tully T, Preat T, Boynton SC, Del Vecchio M. Genetic dissection of consolidated memory in Drosophila. Cell. 1994;79: 35–47. doi: 10.1016/0092-8674(94)90398-0 7923375

19. Isabel G, Pascual A, Preat T. Exclusive Consolidated Memory Phases in Drosophila. Science. 2004;304: 1024–1027. doi: 10.1126/science.1094932 15143285

20. Placais PY, de Tredern E, Scheunemann L, Trannoy S, Goguel V, Han KA, et al. Upregulated energy metabolism in the Drosophila mushroom body is the trigger for long-term memory. Nat Commun. 2017;8: 15510. doi: 10.1038/ncomms15510 28580949

21. Placais PY, Trannoy S, Isabel G, Aso Y, Siwanowicz I, Belliart-Guerin G, et al. Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila. Nat Neurosci. 2012;15: 592–599. doi: 10.1038/nn.3055 22366756

22. Widmann A, Eichler K, Selcho M, Thum ASASS, Pauls D. Odor-taste learning in Drosophila larvae. J Insect Physiol. 2017;106: 47–54. doi: 10.1016/j.jinsphys.2017.08.004 28823531

23. Eichler K, Li F, Litwin-Kumar A, Park Y, Andrade I, Schneider-Mizell CMM, et al. The complete connectome of a learning and memory centre in an insect brain. Nature. 2017;548: 175–182. doi: 10.1038/nature23455 28796202

24. Thum AS, Gerber B. Connectomics and function of a memory network: the mushroom body of larval Drosophila. Curr Opin Neurobiol. 2019;54: 146–154. doi: 10.1016/j.conb.2018.10.007 30368037

25. Widmann A, Artinger M, Biesinger L, Boepple K, Peters C, Schlechter J, et al. Genetic Dissection of Aversive Associative Olfactory Learning and Memory in Drosophila Larvae. PLoS Genet. 2016;12: e1006378. doi: 10.1371/journal.pgen.1006378 27768692

26. Niewalda T, Singhal N, Fiala A, Saumweber T, Wegener S, Gerber B. Salt processing in larval drosophila: Choice, feeding, and learning shift from appetitive to aversive in a concentration-dependent way. Chem Senses. 2008;33: 685–692. doi: 10.1093/chemse/bjn037 18640967

27. Ugrankar R, Theodoropoulos P, Akdemir F, Henne WM, Graff JM. Circulating glucose levels inversely correlate with Drosophila larval feeding through insulin signaling and SLC5A11. Commun Biol. 2018;1: 110. doi: 10.1038/s42003-018-0109-4 30271990

28. Rohwedder A, Pfitzenmaier JE, Ramsperger N, Apostolopoulou AA, Widmann A, Thum AS. Nutritional value-dependent and nutritional value-independent effects on Drosophila melanogaster larval behavior. Chem Senses. 2012;37: 711–2. doi: 10.1093/chemse/bjs055 22695795

29. Folkers E, Drain P, Quinn WG. Radish, a Drosophila mutant deficient in consolidated memory. Proc Natl Acad Sci U S A. 1993;90: 8123–7. doi: 10.1073/pnas.90.17.8123 8367473

30. Honjo K, Furukubo-Tokunaga K. Distinctive Neuronal Networks and Biochemical Pathways for Appetitive and Aversive Memory in Drosophila Larvae. J Neurosci. 2009;29: 852–862. doi: 10.1523/JNEUROSCI.1315-08.2009 19158309

31. Khurana S, Abubaker M Bin, Siddiqi O. Odour avoidance learning in the larva of Drosophila melanogaster. J Biosci. 2009;34: 621–631. doi: 10.1007/s12038-009-0080-9 19920347

32. Livingstone MS, Sziber PP, Quinn WG. Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant. Cell. 1984;37: 205–215. doi: 10.1016/0092-8674(84)90316-7 6327051

33. Garofalo RS. Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol Metab. 2002;13: 156–62. doi: 10.1016/s1043-2760(01)00548-3 11943559

34. Nässel DR, Kubrak OI, Liu Y, Luo J, Lushchak O V. Factors that regulate insulin producing cells and their output in Drosophila. Front Physiol. 2013;4: 252. doi: 10.3389/fphys.2013.00252 24062693

35. Fernandez R, Tabarini D, Azpiazu N, Frasch M, Schlessinger J. The Drosophila insulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential. EMBO J. 1995;14: 3373–84. doi: 10.1002/j.1460-2075.1995.tb07343.x 7628438

36. Tanabe K, Itoh M, Tonoki A. Age-Related Changes in Insulin-like Signaling Lead to Intermediate-Term Memory Impairment in Drosophila. Cell Rep. 2017;18: 1598–1605. doi: 10.1016/j.celrep.2017.01.053 28199832

37. Chambers DB, Androschuk A, Rosenfelt C, Langer S, Harding M, Bolduc F V. Insulin signaling is acutely required for long-term memory in Drosophila. Front Neural Circuits. 2015;9: 1–7. doi: 10.3389/fncir.2015.00001 25713515

38. Luo J, Liu Y, Nässel DR. Insulin/IGF-Regulated Size Scaling of Neuroendocrine Cells Expressing the bHLH Transcription Factor Dimmed in Drosophila. PLoS Genet. 2013;9: e1004052. doi: 10.1371/journal.pgen.1004052 24385933

39. Alyagor I, Berkun V, Keren-Shaul H, Marmor-Kollet N, David E, Mayseless O, et al. Combining Developmental and Perturbation-Seq Uncovers Transcriptional Modules Orchestrating Neuronal Remodeling. Dev Cell. 2018. doi: 10.1016/j.devcel.2018.09.013 30300589

40. Heisenberg M. Mushroom body memoir: From maps to models. Nat Rev Neurosci. 2003;4: 266–275. doi: 10.1038/nrn1074 12671643

41. Zhao XL, Campos AR. Insulin signalling in mushroom body neurons regulates feeding behaviour in Drosophila larvae. J Exp Biol. 2012;215: 2696–702. doi: 10.1242/jeb.066969 22786647

42. Selcho M, Stocker RF, Thum AS, Pauls D, Gendre N, Selcho M, et al. Drosophila Larvae Establish Appetitive Olfactory Memories via Mushroom Body Neurons of Embryonic Origin. J Neurosci. 2010;30: 10655–10666. doi: 10.1523/JNEUROSCI.1281-10.2010 20702697

43. Connolly JB, Roberts IJ, Armstrong JD, Kaiser K, Forte M, Tully T, et al. Associative learning disrupted by impaired Gs signaling in Drosophila mushroom bodies. Science. 1996;274: 2104–2107. doi: 10.1126/science.274.5295.2104 8953046

44. Enell LE, Kapan N, Söderberg JAE, Kahsai L, Nässe DR. Insulin signaling, lifespan and stress resistance are modulated by metabotropic GABA receptors on insulin producing cells in the brain of Drosophila. PLoS One. 2010. doi: 10.1371/journal.pone.0015780 21209905

45. Zars T, Fischer M, Schulz R, Heisenberg M. Localization of a Short-Term Memory in Drosophila. 2000;288.

46. Song W, Ren D, Li W, Jiang L, Cho KW, Huang P, et al. SH2B regulation of growth, metabolism, and longevity in both insects and mammals. Cell Metab. 2010. doi: 10.1016/j.cmet.2010.04.002 20417156

47. Kulansky Poltilove RM, Jacobs AR, Haft CR, Xu P, Taylor SI. Characterization of Drosophila insulin receptor substrate. J Biol Chem. 2000. doi: 10.1074/jbc.M003579200 10801879

48. Tully T, Cambiazo V, Kruse L. Memory through metamorphosis in normal and mutant Drosophila. J Neurosci. 1994;14: 68–74. doi: 10.1523/JNEUROSCI.14-01-00068.1994 8283252

49. Bailey CH, Bartsch D, Kandel ER. Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci U S A. 1996;93: 13445–13452. doi: 10.1073/pnas.93.24.13445 8942955

50. Yin JC, Wallach JS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG, et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell. 1994;79: 49–58. doi: 10.1016/0092-8674(94)90399-9 7923376

51. Bailey CH, Giustetto M, Zhu H, Chen M, Kandel ER. A novel function for serotonin-mediated short-term facilitation in Aplysia: Conversion of a transient, cell-wide homosynaptic Hebbian plasticity into a persistent, protein synthesis-independent synapse-specific enhancement. Proc Natl Acad Sci. 2000;97: 11581–11586. doi: 10.1073/pnas.97.21.11581 11027355

52. Fischer A. Distinct Roles of Hippocampal De Novo Protein Synthesis and Actin Rearrangement in Extinction of Contextual Fear. J Neurosci. 2004;24: 1962–1966. doi: 10.1523/JNEUROSCI.5112-03.2004 14985438

53. Lattal KM, Abel T. Different requirements for protein synthesis in acquisition and extinction of spatial preferences and context-evoked fear. J Neurosci. 2001;21: 5773–5780. 21/15/5773 [pii] doi: 10.1523/JNEUROSCI.21-15-05773.2001 11466449

54. Muller U. Learning in honeybees: from molecules to behaviour. Zool. 2002;105: 313–320. doi: 10.1078/0944-2006-00075 16351880

55. Tully T, Boynton S, Brandes C, Dura JM, Mihalek R, Preat T, et al. Genetic dissection of memory formation in Drosophila melanogaster. Cold Spring Harb Symp Quant Biol. 1990;55: 203–211. doi: 10.1101/sqb.1990.055.01.022 2132815

56. Aguila JR, Hoshizaki DK, Gibbs AG. Contribution of larval nutrition to adult reproduction in Drosophila melanogaster. J Exp Biol. 2013;216: 399–406. doi: 10.1242/jeb.078311 23038728

57. Wu CL, Chang CC, Wu JK, Chiang MH, Yang CH, Chiang HC. Mushroom body glycolysis is required for olfactory memory in Drosophila. Neurobiol Learn Mem. 2018;150: 13–19. doi: 10.1016/j.nlm.2018.02.015 29477608

58. Gold PE, Korol DL. Making Memories Matter. Front Integr Neurosci. 2012;6: 1–11. doi: 10.3389/fnint.2012.00001 22319479

59. Owusu-Ansah E, Perrimon N. Modeling metabolic homeostasis and nutrient sensing in Drosophila: Implications for aging and metabolic diseases. DMM Disease Models and Mechanisms. 2014. doi: 10.1242/dmm.012989 24609035

60. Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, et al. Minibrain/Dyrk1a Regulates Food Intake through the Sir2-FOXO-sNPF/NPY Pathway in Drosophila and Mammals. PLoS Genet. 2012. doi: 10.1371/journal.pgen.1002857 22876196

61. Lee G, Park JH. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster. Genetics. 2004. doi: 10.1534/genetics.167.1.311 15166157

62. Wu Q, Zhao Z, Shen P. Regulation of aversion to noxious food by Drosophila neuropeptide Y–and insulin-like systems. Nat Neurosci. 2005;8: 1350–1355. doi: 10.1038/nn1540 16172603

63. Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64: 3927–36. doi: 10.2337/db15-0596 26216852

64. Suarez AN, Noble EE, Kanoski SE. Regulation of memory function by feeding-relevant biological systems: Following the breadcrumbs to the hippocampus. Front Mol Neurosci. 2019;12: 101. doi: 10.3389/fnmol.2019.00101 31057368

65. Claeys I, Simonet G, Poels J, Van Loy T, Vercammen L, De Loof A, et al. Insulin-related peptides and their conserved signal transduction pathway. Peptides. 2002;23: 807–16. doi: 10.1016/s0196-9781(01)00666-0 11897402

66. Kandel ER. The biology of memory: A forty-year perspective. J Neurosci. 2009;29: 12748–12756. doi: 10.1523/JNEUROSCI.3958-09.2009 19828785

67. Wu Q, Zhang Y, Xu J, Shen P. Regulation of hunger-driven behaviors by neural ribosomal S6 kinase in Drosophila. Proc Natl Acad Sci U S A. 2005;102: 13289–13294. doi: 10.1073/pnas.0501914102 16150727

68. Yu D, Akalal DBG, Davis RL. Drosophila α/β Mushroom Body Neurons Form a Branch-Specific, Long-Term Cellular Memory Trace after Spaced Olfactory Conditioning. Neuron. 2006. doi: 10.1016/j.neuron.2006.10.030 17145505

69. Scherer S, Stocker RF, Gerber B. Olfactory learning in individually assayed Drosophila larvae. Learn Mem. 2003;10: 217–225. doi: 10.1101/lm.57903 12773586

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 10

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Antiseptika a prevence ve stomatologii
nový kurz
Autoři: MUDr. Ladislav Korábek, CSc., MBA

Diagnostika a léčba deprese pro ambulantní praxi
Autoři: MUDr. Jan Hubeňák, Ph.D

Snímatelné zubní náhrady a fixační krémy
Autoři: doc. MUDr. Hana Hubálková, Ph.D.

Nová éra v léčbě migrény
Autoři: MUDr. Eva Medová, MUDr. Tomáš Nežádal, Ph.D.

Význam nutraceutik u kardiovaskulárních onemocnění

Všechny kurzy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se