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Serotonin and neuropeptide F have opposite modulatory effects on fly aggression


Both serotonin (5-HT) and neuropeptide Y have been shown to affect a variety of mammalian behaviors1,2,3, including aggression4,5. Here we show in Drosophila melanogaster that both 5-HT and neuropeptide F, the invertebrate homolog of neuropeptide Y, modulate aggression. We show that drug-induced increases of 5-HT in the fly brain increase aggression. Elevating 5-HT genetically in the serotonergic circuits recapitulates these pharmacological effects, whereas genetic silencing of these circuits makes the flies behaviorally unresponsive to the drug-induced increase of 5-HT but leaves them capable of aggression. Genetic silencing of the neuropeptide F (npf) circuit also increases fly aggression, demonstrating an opposite modulation to 5-HT. Moreover, this neuropeptide F effect seems to be independent of 5-HT. The implication of these two modulatory systems in fly and mouse aggression suggest a marked degree of conservation and a deep molecular root for this behavior.

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Figure 1: Fighting frequency and pharmacological manipulation of 5-HT levels in fly heads from generation 38.
Figure 2: 5-HTP increases aggression in a linear manner in the selected lines.
Figure 3: Genetic elevation of 5-HT increases aggression, and genetic silencing of the 5-HT circuit makes flies unresponsive to 5-HTP.
Figure 4: Genetic silencing of the npf circuit increases aggression independently of 5-HTP–induced aggression.


  1. Lucki, I. The spectrum of behaviors influenced by serotonin. Biol. Psychiatry 44, 151–162 (1998).

    CAS  Article  PubMed  Google Scholar 

  2. Pedrazzini, T., Pralong, F. & Grouzmann, E. NPY: the universal soldier. Cell. Mol. Life Sci. 60, 350–377 (2003).

    CAS  Article  PubMed  Google Scholar 

  3. Carvajal, C., Dumont, Y. & Quirion, R. Neuropeptide y: role in emotion and alcohol dependence. CNS Neurol. Disord. Drug Targets 5, 181–195 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. Popova, N.K. From genes to aggressive behavior: the role of the serotonergic system. Bioessays 28, 495–503 (2006).

    CAS  Article  PubMed  Google Scholar 

  5. Karl, T. et al. Y1 receptors regulate aggressive behavior by modulating serotonin pathways. Proc. Natl. Acad. Sci. USA 101, 12742–12747 (2004).

    CAS  Article  PubMed  Google Scholar 

  6. Kravitz, E.A. & Huber, R. Aggression in invertebrates. Curr. Opin. Neurobiol. 13, 736–743 (2003).

    CAS  Article  PubMed  Google Scholar 

  7. Yuan, Q., Joiner, W.J. & Sehgal, A. A sleep promoting role for the Drosophila serotonin receptor 1A. Curr. Biol. 16, 1051–1062 (2006).

    CAS  Article  PubMed  Google Scholar 

  8. Yuan, Q., Lin, F., Zheng, X. & Sehgal, A. Serotonin modulates circadian entrainment in Drosophila. Neuron 47, 115–127 (2005).

    CAS  Article  PubMed  Google Scholar 

  9. Wen, T., Parrish, C.A., Xu, D., Wu, Q. & Shen, P. Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity. Proc. Natl. Acad. Sci. USA 102, 2141–2146 (2005).

    CAS  Article  PubMed  Google Scholar 

  10. Wu, Q., Zhao, Z. & Shen, P. Regulation of aversion to noxious food by Drosophila neuropeptide Y- and insulin-like systems. Nat. Neurosci. 8, 1350–1355 (2005).

    CAS  Article  PubMed  Google Scholar 

  11. Lee, G., Bahn, J.H. & Park, J.H. Sex- and clock-controlled expression of the neuropeptide F gene in Drosophila. Proc. Natl. Acad. Sci. USA 103, 12580–12585 (2006).

    CAS  Article  PubMed  Google Scholar 

  12. Baier, A., Wittek, B. & Brembs, B. Drosophila as a new model organism for the neurobiology of aggression? J. Exp. Biol. 205, 1233–1240 (2002).

    PubMed  Google Scholar 

  13. Stevenson, P.A., Hofmann, H.A., Schoch, K. & Schildberger, K. The fight and flight responses of crickets depleted of biogenic amines. J. Neurobiol. 43, 107–120 (2000).

    CAS  Article  PubMed  Google Scholar 

  14. Dierick, H.A. & Greenspan, R.J. Molecular analysis of flies selected for aggressive behavior. Nat. Genet. 38, 1023–1031 (2006).

    CAS  Article  PubMed  Google Scholar 

  15. Monastirioti, M. Biogenic amine systems in the fruit fly Drosophila melanogaster. Microsc. Res. Tech. 45, 106–121 (1999).

    CAS  Article  PubMed  Google Scholar 

  16. 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  Google Scholar 

  17. Li, H., Chaney, S., Roberts, I.J., Forte, M. & Hirsh, J. Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Curr. Biol. 10, 211–214 (2000).

    CAS  Article  PubMed  Google Scholar 

  18. Coleman, C.M. & Neckameyer, W.S. Serotonin synthesis by two distinct enzymes in Drosophila melanogaster. Arch. Insect Biochem. Physiol. 59, 12–31 (2005).

    CAS  Article  PubMed  Google Scholar 

  19. Lundell, M.J. & Hirsh, J. Temporal and spatial development of serotonin and dopamine neurons in the Drosophila CNS. Dev. Biol. 165, 385–396 (1994).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  21. Suster, M.L., Martin, J.-R., Sung, C. & Robinow, S. Targeted expression of tetanos toxin reveals sets of neurons involved in larval locomotion in Drosophila. J. Neurobiol. 55, 233–246 (2003).

    CAS  Article  PubMed  Google Scholar 

  22. Nilsen, S.P., Chan, Y.B., Huber, R. & Kravitz, E.A. Gender-selective patterns of aggressive behavior in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 101, 12342–12347 (2004).

    CAS  Article  PubMed  Google Scholar 

  23. Vrontou, E., Nilsen, S.P., Demir, E., Kravitz, E.A. & Dickson, B.J. fruitless regulates aggression and dominance in Drosophila. Nat. Neurosci. 9, 1469–1471 (2006).

    CAS  Article  PubMed  Google Scholar 

  24. Ferveur, J.F., Stortkuhl, K.F., Stocker, R.F. & Greenspan, R.J. Genetic feminization of brain structures and changed sexual orientation in male Drosophila. Science 267, 902–905 (1995).

    CAS  Article  PubMed  Google Scholar 

  25. Karess, R.E. & Rubin, G.M. Analysis of transposable element function in Drosophila. Cell 38, 135–146 (1984).

    CAS  Article  PubMed  Google Scholar 

  26. Slemmon, J.R., Salvaterra, P.M., Crawford, G.D. & Roberts, E. Purification of cholineacetyltransferase from Drosophila melanogaster. J. Biol. Chem. 257, 3847–3852 (1982).

    CAS  PubMed  Google Scholar 

  27. Lindsey, J.W., Jung, A.E., Narayanan, T.K. & Ritchie, G.D. Acute effects of a bicyclophosphate neuroconvulsant on monoamine neurotransmitter and metabolite levels in the rat brain. J. Toxicol. Environ. Health A 54, 421–429 (1998).

    CAS  Article  PubMed  Google Scholar 

  28. Cransac, H., Cottett-Emard, J.-M., Pequignot, J.M. & Peyrin, L. Monoamines (norepinephrine, dopamine, serotonin) in the rat medial vestibular nucleus: endogenous levels and turnover. J. Neural Transm. 103, 391–401 (1996).

    CAS  Article  PubMed  Google Scholar 

  29. Hoffmann, A.A. The influence of age and experience with conspecifics on territorial behavior in Drosophila melanogaster. J. Insect Behav. 3, 1–12 (1990).

    Article  Google Scholar 

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We thank J. Sullivan for help with behavioral analysis, D. Robinson for technical assistance, R. Johnson for 5-HT analysis by HPLC and B. van Swinderen, R. Andretic and S. Pangas for comments on the manuscript. We also thank P. Shen (University of Georgia) for the npf-GAL4 stock and T. Stone (University of California, San Diego) for generating the UAS-dTrh transformants. Ddc-GAL4/TM3, Ser and Th-GAL4/TM3, Ser were provided by J. Hirsch (University of Virginia). UAS-TNT was provided by U. Heberlein (University of San Francisco). This material is based on work supported by the US National Science Foundation under grant number 0432063 (R.J.G. and H.A.D.). R.J.G. is the Dorothy and Lewis B. Cullman Fellow at The Neurosciences Institute, which is supported by the Neurosciences Research Foundation.

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Authors and Affiliations



This study was designed by H.A.D. and R.J.G. H.A.D. performed the experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Herman A Dierick.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Escalating flies and aggression measurement. (PDF 56 kb)

Supplementary Fig. 2

Schematic of 5-HT synthesis. (PDF 22 kb)

Supplementary Fig. 3

Linear regression plot of fighting frequencies of treated and untreated lines. (PDF 28 kb)

Supplementary Table 1

Gene products involved in 5-HT function and their mammalian homologs. (PDF 14 kb)

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Dierick, H., Greenspan, R. Serotonin and neuropeptide F have opposite modulatory effects on fly aggression. Nat Genet 39, 678–682 (2007).

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