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Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila

Nature Neuroscience volume 15, pages 592–599 (2012)Cite this article

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Abstract

A fundamental duty of any efficient memory system is to prevent long-lasting storage of poorly relevant information. However, little is known about dedicated mechanisms that appropriately trigger production of long-term memory (LTM). We examined the role of Drosophila dopaminergic neurons in the control of LTM formation and found that they act as a switch between two exclusive consolidation pathways leading to LTM or anesthesia-resistant memory (ARM). Blockade, after aversive olfactory conditioning, of three pairs of dopaminergic neurons projecting on mushroom bodies, the olfactory memory center, enhanced ARM, whereas their overactivation conversely impaired ARM. Notably, blockade of these neurons during the intertrial intervals of a spaced training precluded LTM formation. Two pairs of these dopaminergic neurons displayed sustained calcium oscillations in naive flies. Oscillations were weakened by ARM-inducing massed training and were enhanced during LTM formation. Our results indicate that oscillations of two pairs of dopaminergic neurons control ARM levels and gate LTM.

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Figure 1: Th-GAL4 neurons regulate ARM consolidation.
Figure 2: Three pairs of dopaminergic neurons recapitulate the ARM-regulating properties of Th-GAL4 neurons.
Figure 3: Spontaneous sustained activity in MV1 and MP1 neurons of naive flies.
Figure 4: Oscillations in MV1 and MP1 neurons are correlated with ARM regulation.
Figure 5: ARM is absent after spaced conditioning.
Figure 6: Spaced training consistently promotes oscillatory behavior in MV1 and MP1 neurons.
Figure 7: ARM-inhibiting neurons gate long-term memory formation.

References

  1. Neumann, N. et al. The mind of the mnemonists: an MEG and neuropsychological study of autistic memory savants. Behav. Brain Res. 215, 114–121 (2010).

    Article  Google Scholar 

  2. Treffert, D.A. The savant syndrome: an extraordinary condition. A synopsis: past, present, future. Phil. Trans. R. Soc. Lond. B 364, 1351–1357 (2009).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Mery, F. & Kawecki, T.J. A cost of long-term memory in Drosophila. Science 308, 1148 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Wise, R.A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494 (2004).

    Article  CAS  Google Scholar 

  8. O'Carroll, C.M., Martin, S.J., Sandin, J., Frenguelli, B. & Morris, R.G.M. Dopaminergic modulation of the persistence of one-trial hippocampus-dependent memory. Learn. Mem. 13, 760–769 (2006).

    Article  CAS  Google Scholar 

  9. Bethus, I., Tse, D. & Morris, R.G.M. Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates. J. Neurosci. 30, 1610–1618 (2010).

    Article  CAS  Google Scholar 

  10. Rossato, J.I., Bevilaqua, L.R.M., Izquierdo, I., Medina, J.H. & Cammarota, M. Dopamine controls persistence of long-term memory storage. Science 325, 1017–1020 (2009).

    Article  CAS  Google Scholar 

  11. Waddell, S. Dopamine reveals neural circuit mechanisms of fly memory. Trends Neurosci. 33, 457–464 (2010).

    Article  CAS  Google Scholar 

  12. Riemensperger, T. et al. Behavioral consequences of dopamine deficiency in the Drosophila central nervous system. Proc. Natl. Acad. Sci. USA 108, 834–839 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Keene, A.C. & Waddell, S. Drosophila olfactory memory: single genes to complex neural circuits. Nat. Rev. Neurosci. 8, 341–354 (2007).

    Article  CAS  Google Scholar 

  15. Schwaerzel, M. et al. Dopamine and octopamine differentiate between aversive and appetitive olfactory memories in Drosophila. J. Neurosci. 23, 10495–10502 (2003).

    Article  CAS  Google Scholar 

  16. Claridge-Chang, A. et al. Writing memories with light-addressable reinforcement circuitry. Cell 139, 405–415 (2009).

    Article  CAS  Google Scholar 

  17. Aso, Y. et al. Specific dopaminergic neurons for the formation of labile aversive memory. Curr. Biol. 20, 1445–1451 (2010).

    Article  CAS  Google Scholar 

  18. Zhang, S., Yin, Y., Lu, H. & Guo, A. Increased dopaminergic signaling impairs aversive olfactory memory retention in Drosophila. Biochem. Biophys. Res. Commun. 370, 82–86 (2008).

    Article  CAS  Google Scholar 

  19. Mao, Z. & Davis, R.L. Eight different types of dopaminergic neurons innervate the Drosophila mushroom body neuropil: anatomical and physiological heterogeneity. Front. Neural Circuits 3, 5 (2009).

    Article  Google Scholar 

  20. Heisenberg, M. Mushroom body memoir: from maps to models. Nat. Rev. Neurosci. 4, 266–275 (2003).

    Article  CAS  Google Scholar 

  21. Tanaka, N.K., Tanimoto, H. & Ito, K. Neuronal assemblies of the Drosophila mushroom body. J. Comp. Neurol. 508, 711–755 (2008).

    Article  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. Krashes, M.J. et al. A neural circuit mechanism integrating motivational state with memory expression in Drosophila. Cell 139, 416–427 (2009).

    Article  CAS  Google Scholar 

  24. Friggi-Grelin, F. et al. Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J. Neurobiol. 54, 618–627 (2003).

    Article  CAS  Google Scholar 

  25. Folkers, E., Drain, P. & Quinn, W.G. Radish, a Drosophila mutant deficient in consolidated memory. Proc. Natl. Acad. Sci. USA 90, 8123–8127 (1993).

    Article  CAS  Google Scholar 

  26. Tian, L. et al. Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators. Nat. Methods 6, 875–881 (2009).

    Article  CAS  Google Scholar 

  27. Folkers, E., Waddell, S. & Quinn, W.G. The Drosophila radish gene encodes a protein required for anesthesia-resistant memory. Proc. Natl. Acad. Sci. USA 103, 17496–17500 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Didelot, G. et al. Tequila, a neurotrypsin ortholog, regulates long-term memory formation in Drosophila. Science 313, 851–853 (2006).

    Article  CAS  Google Scholar 

  30. Lee, P.-T. et al. Serotonin-mushroom body circuit modulating the formation of anesthesia-resistant memory in Drosophila. Proc. Natl. Acad. Sci. USA 108, 13794–13799 (2011).

    Article  CAS  Google Scholar 

  31. Yin, J.C., Del Vecchio, M., Zhou, H. & Tully, T. CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107–115 (1995).

    Article  CAS  Google Scholar 

  32. Horiuchi, J., Yamazaki, D., Naganos, S., Aigaki, T. & Saitoe, M. Protein kinase A inhibits a consolidated form of memory in Drosophila. Proc. Natl. Acad. Sci. USA 105, 20976–20981 (2008).

    Article  CAS  Google Scholar 

  33. Gervasi, N., Tchénio, P. & Preat, T. PKA dynamics in a Drosophila learning center: coincidence detection by rutabaga adenylyl cyclase and spatial regulation by dunce phosphodiesterase. Neuron 65, 516–529 (2010).

    Article  CAS  Google Scholar 

  34. Tomchik, S.M. & Davis, R.L. Dynamics of learning-related cAMP signaling and stimulus integration in the Drosophila olfactory pathway. Neuron 64, 510–521 (2009).

    Article  CAS  Google Scholar 

  35. Pagani, M.R., Oishi, K., Gelb, B.D. & Zhong, Y. The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 139, 186–198 (2009).

    Article  CAS  Google Scholar 

  36. Lyons, D.J., Horjales-Araujo, E. & Broberger, C. Synchronized network oscillations in rat tuberoinfundibular dopamine neurons: switch to tonic discharge by thyrotropin-releasing hormone. Neuron 65, 217–229 (2010).

    Article  CAS  Google Scholar 

  37. Shi, W.-X. Slow oscillatory firing: a major firing pattern of dopamine neurons in the ventral tegmental area. J. Neurophysiol. 94, 3516–3522 (2005).

    Article  CAS  Google Scholar 

  38. Gao, M. et al. Functional coupling between the prefrontal cortex and dopamine neurons in the ventral tegmental area. J. Neurosci. 27, 5414–5421 (2007).

    Article  CAS  Google Scholar 

  39. Benchenane, K. et al. Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning. Neuron 66, 921–936 (2010).

    Article  CAS  Google Scholar 

  40. Pascual, A. & Préat, T. Localization of long-term memory within the Drosophila mushroom body. Science 294, 1115–1117 (2001).

    Article  CAS  Google Scholar 

  41. Séjourné, J. et al. Mushroom body efferent neurons responsible for aversive olfactory memory retrieval in Drosophila. Nat. Neurosci. 14, 903–910 (2011).

    Article  Google Scholar 

  42. Yu, D., Akalal, D.-B.G. & Davis, R.L. Drosophila α/β mushroom body neurons form a branch-specific, long-term cellular memory trace after spaced olfactory conditioning. Neuron 52, 845–855 (2006).

    Article  CAS  Google Scholar 

  43. Otsuna, H. & Ito, K. Systematic analysis of the visual projection neurons of Drosophila melanogaster. I. Lobula-specific pathways. J. Comp. Neurol. 497, 928–958 (2006).

    Article  Google Scholar 

  44. Plaçais, P.-Y., Balland, M., Guérin, T., Joanny, J.-F. & Martin, P. Spontaneous oscillations of a minimal actomyosin system under elastic loading. Phys. Rev. Lett. 103, 158102 (2009).

    Article  Google Scholar 

  45. Rivals, I., Personnaz, L., Taing, L. & Potier, M.-C. Enrichment or depletion of a GO category within a class of genes: which test? Bioinformatics 23, 401–407 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Pascual (Instituto de Biomedicina de Sevilla) and members of the Genes and Dynamics of Memory Systems group for critical reading of the manuscript. This work was supported by grants from the Agence Nationale pour la Recherche (T.P.), the Fondation pour la Recherche Médicale (T.P.), the Fondation Bettencourt-Schueller (T.P.), the Emmy-Noether Program from Deutsche Forschungsgemeinschaft (H.T.), the Bernstein focus Learning from Bundesministerium für Bildung und Forschung (H.T.) and the Max-Planck-Gesellschaft (H.T.). P.-Y.P. was supported by a grant from Région Ile-de-France, G.I. and S.T. by the Fondation pour la Recherche Médicale, and Y.A. by Deutscher Akademischer Austausch Dienst.

Author information

Author notes

  1. Guillaume Isabel & Yoshinori Aso

    Present address: Present addresses: Centre de Recherches sur la Cognition Animale, Université Paul Sabatier, Toulouse, France (G.I.) and Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia, USA (Y.A.).,

  2. Pierre-Yves Plaçais, Séverine Trannoy and Guillaume Isabel: These authors contributed equally to this work.

Authors and Affiliations

  1. Genes and Dynamics of Memory Systems, Neurobiology Unit, Centre National de la Recherche Scientifique, École Supérieure de Physique et de Chimie Industrielles (ESPCI), Paris, France

    Pierre-Yves Plaçais, Séverine Trannoy, Guillaume Isabel, Ghislain Belliart-Guérin & Thomas Preat

  2. Behavioral Genetics, Max Planck Institute of Neurobiology, Martinsried, Germany

    Yoshinori Aso, Igor Siwanowicz & Hiromu Tanimoto

  3. Développement, Evolution, Plasticité du Système Nerveux, Institut de Neurobiologie Alfred-Fessard, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France

    Philippe Vernier

  4. Genetics and Physiopathology of Neurotransmission, Neurobiology Unit, Centre National de la Recherche Scientifique, ESPCI, Paris, France

    Serge Birman

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Contributions

S.B., G.I. and T.P. were involved in the original design of the study. Behavioral experiments were performed by G.I. (Figs. 1, 5a and 7a, and Supplementary Fig. 1), S.T. (Figs. 2, 5c,d and 7b,d,e, and Supplementary Figs. 2 and 7), P.-Y.P. (Fig. 5b and Supplementary Fig. 5a) and G.B.-G. (Supplementary Fig. 6c). P.-Y.P. carried out all of the calcium imaging experiments and data analyses, except for the rsh experiment that was perfomed by G.B.-G. (Supplementary Fig. 6a,b). Y.A., I.S. and H.T. performed immunohistochemistry and analyzed the results. S.B. provided some fly stocks. P.V. provided financial support. P.-Y.P. and T.P. wrote the manuscript. T.P. designed the study and supervised the work. All of the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Thomas Preat.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 2867 kb)

Supplementary Movie 1

Confocal stack showing the NP47-GAL4 expression pattern visualized by mCD8::GFP (white). Neuropils are counterlabeled with an anti-synapsin antibody (orange). (AVI 3264 kb)

Supplementary Movie 2

Confocal stack showing the NP47-GAL4 expression pattern visualized by mCD8::GFP (white). TH immunoreactive cells are labeled in magenta. (AVI 2811 kb)

Supplementary Movie 3

Confocal stack showing the NP47-GAL4 expression pattern, in combination with TH-GAL80, visualized by mCD8::GFP (white). Neuropils are counterlabeled with an anti-synapsin antibody (orange). (AVI 2962 kb)

Supplementary Movie 4

Confocal stack showing the NP47-GAL4 expression pattern, in combination with TH-GAL80, visualized by mCD8::GFP (white). TH immunoreactive cells are labeled in magenta. (AVI 2600 kb)

Supplementary Movie 5

Spontaneous activity oscillations in MB projections from MV1/MP1 neurons. This movie is accelerated 10 times; the real duration of the recording was 330 s. Oscillation characteristics were: left hemisphere: f0 = 0.11 Hz, Q = 2.1, amplitude 29% and right hemisphere: f0 = 0.105 Hz, Q = 1.6 amplitude 32%. Raw 8-bit grayscale images were smoothed with a 2-pixel radius Gaussian filter, a constant value of 30 was substracted from the resulting whole images, and contrast was then enhanced by rescaling intensity to reach 1.5% saturated pixels on one oscillation peak image (image processing performed with ImageJ). (AVI 3391 kb)

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Plaçais, PY., Trannoy, S., Isabel, G. et al. Slow oscillations in two pairs of dopaminergic neurons gate long-term memory formation in Drosophila. Nat Neurosci 15, 592–599 (2012). https://doi.org/10.1038/nn.3055

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