Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Specific requirement of NMDA receptors for long-term memory consolidation in Drosophila ellipsoid body

Abstract

In humans and many other animals, memory consolidation occurs through multiple temporal phases and usually involves more than one neuroanatomical brain system. Genetic dissection of Pavlovian olfactory learning in Drosophila melanogaster has revealed multiple memory phases, but the predominant view holds that all memory phases occur in mushroom body neurons. Here, we demonstrate an acute requirement for NMDA receptors (NMDARs) outside of the mushroom body during long-term memory (LTM) consolidation. Targeted dsRNA-mediated silencing of Nmdar1 and Nmdar2 (also known as dNR1 or dNR2, respectively) in cholinergic R4m-subtype large-field neurons of the ellipsoid body specifically disrupted LTM consolidation, but not retrieval. Similar silencing of functional NMDARs in the mushroom body disrupted an earlier memory phase, leaving LTM intact. Our results clearly establish an anatomical site outside of the mushroom body involved with LTM consolidation, thus revealing both a distributed brain system subserving olfactory memory formation and the existence of a system-level memory consolidation in Drosophila.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: dsRNA-mediated knockdown of dNR2 in adult brain.
Figure 2: Functional NMDARs in the ellipsoid body are required for LTM.
Figure 3: Inducible knockdown of dNR2 specifically blocks consolidation and storage, but not retrieval, of protein synthesis–dependent LTM.
Figure 4: Overexpression of dNR2 in the ellipsoid body enhances 1-d memory.
Figure 5: Transference of memory from the mushroom body to the ellipsoid body during LTM consolidation.
Figure 6: NMDAR function in the mushroom body is required for MTM but not for LTM.

References

  1. 1

    Xia, S. et al. NMDA receptors mediate olfactory learning and memory in Drosophila. Curr. Biol. 15, 603–615 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Roberts, A.C. & Glanzman, D.L. Learning in Aplysia: looking at synaptic plasticity from both sides. Trends Neurosci. 26, 662–670 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Tsien, J.Z. Linking Hebb's coincidence-detection to memory formation. Curr. Opin. Neurobiol. 10, 266–273 (2000).

    CAS  Article  Google Scholar 

  4. 4

    Allweis, C. The congruity of rat and chick multiphase memory-consolidation models. In Neural and Behavioral Plasticity (ed. Andrew, R.J.) 370–393 (Oxford University Press, New York, 1991).

    Google Scholar 

  5. 5

    Davis, R.L. Olfactory memory formation in Drosophila: from molecular to systems neuroscience. Annu. Rev. Neurosci. 28, 275–302 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Margulies, C., Tully, T. & Dubnau, J. Deconstructing memory in Drosophila. Curr. Biol. 15, R700–R713 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Kogan, J.H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Tully, T., Preat, T., Boynton, S.C. & Del Vecchio, M. Genetic dissection of consolidated memory in Drosophila. Cell 79, 35–47 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Eichenbaum, H. & Cohen, N.J. From Conditioning to Conscious Recollection: Memory Systems of the Brain 583 (Oxford University Press, New York, 2001).

    Google Scholar 

  10. 10

    Gerber, B., Tanimoto, H. & Heisenberg, M. An engram found? Evaluating the evidence from fruit flies. Curr. Opin. Neurobiol. 14, 737–744 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Stocker, R.F. The organization of the chemosensory system in Drosophila melanogaster: a review. Cell Tissue Res. 275, 3–26 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Jefferis, G.S., Marin, E.C., Watts, R.J. & Luo, L. Development of neuronal connectivity in Drosophila antennal lobes and mushroom bodies. Curr. Opin. Neurobiol. 12, 80–86 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Hanesch, U., Fischback, K.-F. & Heisenberg, M. Neuronal architecture of the central complex in Drosophila melanogaster. Cell Tissue Res. 257, 343–366 (1989).

    Article  Google Scholar 

  14. 14

    Strauss, R. & Heisenberg, M. A higher control center of locomotor behavior in the Drosophila brain. J. Neurosci. 13, 1852–1861 (1993).

    CAS  Article  Google Scholar 

  15. 15

    Comas, D., Petit, F. & Preat, T. Drosophila long-term memory formation involves regulation of cathepsin activity. Nature 430, 460–463 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Dubnau, J. et al. The staufen/pumilio pathway is involved in Drosophila long-term memory. Curr. Biol. 13, 286–296 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Waddell, S., Armstrong, J.D., Kitamoto, T., Kaiser, K. & Quinn, W.G. The amnesiac gene product is expressed in two neurons in the Drosophila brain that are critical for memory. Cell 103, 805–813 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Pascual, A., Huang, K.L., Neveu, J. & Preat, T. Neuroanatomy: brain asymmetry and long-term memory. Nature 427, 605–606 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Kitamoto, T. Conditional modification of behavior in Drosophila by targeted expression of a temperature-sensitive shibire allele in defined neurons. J. Neurobiol. 47, 81–92 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Brand, A.H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Carthew, R.W. Gene silencing by double-stranded RNA. Curr. Opin. Cell Biol. 13, 244–248 (2001).

    CAS  Article  Google Scholar 

  22. 22

    Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Hannon, G.J. RNA interference. Nature 418, 244–251 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Flockhart, I. et al. Fly RNAi: the Drosophila RNAi screening center database. Nucleic Acids Res. 34, D489–D494 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Liu, G. et al. Distinct memory traces for two visual features in the Drosophila brain. Nature 439, 551–556 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Sakai, T., Tamura, T., Kitamoto, T. & Kidokoro, Y. A clock gene, period, plays a key role in long-term memory formation in Drosophila. Proc. Natl. Acad. Sci. USA 101, 16058–16063 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Siegmund, T. & Korge, G. Innervation of the ring gland of Drosophila melanogaster. J. Comp. Neurol. 431, 481–491 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Renn, S.C. et al. Genetic analysis of the Drosophila ellipsoid body neuropil: organization and development of the central complex. J. Neurobiol. 41, 189–207 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Yin, J.C. et al. Induction of a dominant-negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994).

    CAS  Article  Google Scholar 

  30. 30

    McGuire, S.E., Le, P.T., Osborn, A.J., Matsumoto, K. & Davis, R.L. Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302, 1765–1768 (2003).

    CAS  Article  Google Scholar 

  31. 31

    Tang, Y.P. et al. Genetic enhancement of learning and memory in mice. Nature 401, 63–69 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Lee, T., Lee, A. & Luo, L. Development of the Drosophila mushroom bodies: sequential generation of three distinct types of neurons from a neuroblast. Development 126, 4065–4076 (1999).

    CAS  Google Scholar 

  33. 33

    Dash, P.K., Hebert, A.E. & Runyan, J.D. A unified theory for systems and cellular memory consolidation. Brain Res. Brain Res. Rev. 45, 30–37 (2004).

    Article  Google Scholar 

  34. 34

    Isabel, G., Pascual, A. & Preat, T. Exclusive consolidated memory phases in Drosophila. Science 304, 1024–1027 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Yu, D., Keene, A.C., Srivatsan, A., Waddell, S. & Davis, R.L. Drosophila DPM neurons form a delayed and branch-specific memory trace after olfactory classical conditioning. Cell 123, 945–957 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Nakazawa, K., McHugh, T.J., Wilson, M.A. & Tonegawa, S. NMDA receptors, place cells and hippocampal spatial memory. Nat. Rev. Neurosci. 5, 361–372 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Akalal, D.B. et al. Roles for Drosophila mushroom body neurons in olfactory learning and memory. Learn. Mem. 13, 659–668 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Dubnau, J., Grady, L., Kitamoto, T. & Tully, T. Disruption of neurotransmission in Drosophila mushroom body blocks retrieval, but not acquisition, of memory. Nature 411, 476–480 (2001).

    CAS  Article  Google Scholar 

  39. 39

    McGuire, S.E., Le, P.T. & Davis, R.L. The role of Drosophila mushroom body signaling in olfactory memory. Science 293, 1330–1333 (2001).

    CAS  Article  Google Scholar 

  40. 40

    Krashes, M.J., Keene, A.C., Leung, B., Armstrong, J.D. & Waddell, S. Sequential use of mushroom body neuron subsets during Drosophila odor memory processing. Neuron 53, 103–115 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Dudai, Y. The neurobiology of consolidations, or, how stable is the engram? Annu. Rev. Psychol. 55, 51–86 (2004).

    Article  Google Scholar 

  42. 42

    Frankland, P.W. & Bontempi, B. The organization of recent and remote memories. Nat. Rev. Neurosci. 6, 119–130 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Wiltgen, B.J., Brown, R.A., Talton, L.E. & Silva, A.J. New circuits for old memories: the role of the neocortex in consolidation. Neuron 44, 101–108 (2004).

    CAS  Article  Google Scholar 

  44. 44

    Xia, S. & Tully, T. Segregation of odor identity and intensity during odor discrimination in Drosophila mushroom body. PLoS Biol. 5, e264 (2007).

    Article  Google Scholar 

  45. 45

    Feany, M.B. & Quinn, W.G. A neuropeptide gene defined by the Drosophila memory mutant amnesiac. Science 268, 869–873 (1995).

    CAS  Article  Google Scholar 

  46. 46

    Keene, A.C. et al. Diverse odor-conditioned memories require uniquely timed dorsal paired medial neuron output. Neuron 44, 521–533 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Emptage, N.J. & Carew, T.J. Long-term synaptic facilitation in the absence of short-term facilitation in Aplysia neurons. Science 262, 253–256 (1993).

    CAS  Article  Google Scholar 

  48. 48

    Tully, T. & Quinn, W.G. Classical conditioning and retention in normal and mutant Drosophila melanogaster. J. Comp. Physiol. [A] 157, 263–277 (1985).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank G. Korge, Y. Zhong, L. Luo and Bloomington Fly Center for fly stocks. We also thank M. Heisenberg, H. Cline and J. Dubnau for comments and discussion. This work was supported by grants to T.T. from the US National Institutes of Health and Dart Neurosciences, LLC, and to A.-S.C. from the National Science Council, the Brain Research Center of the University System of Taiwan and the Technology Development Program of Ministry of Economy.

Author information

Affiliations

Authors

Contributions

C.-L.W. and S.X. conceived and designed the experiments. C.-L.W., S.X. and T.-F.F. carried out the experiments with technique support from H.W., D.L. and Y.-H.C. C.-L.W., S.X. and A.-S.C. analyzed the data. C.-L.W. and S.X. graphed the data. S.X. and T.T. wrote the paper.

Corresponding authors

Correspondence to Ann-Shyn Chiang or Tim Tully.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Table 1 and Methods (PDF 1995 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wu, CL., Xia, S., Fu, TF. et al. Specific requirement of NMDA receptors for long-term memory consolidation in Drosophila ellipsoid body. Nat Neurosci 10, 1578–1586 (2007). https://doi.org/10.1038/nn2005

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing