Functional identification of sensory mechanisms required for developmental song learning

Article metrics


A young male zebra finch (Taeniopygia guttata) learns to sing by copying the vocalizations of an older tutor in a process that parallels human speech acquisition. Brain pathways that control song production are well defined, but little is known about the sites and mechanisms of tutor song memorization. Here we test the hypothesis that molecular signaling in a sensory brain area outside of the song system is required for developmental song learning. Using controlled tutoring and a pharmacological inhibitor, we transiently suppressed the extracellular signal–regulated kinase signaling pathway in a portion of the auditory forebrain specifically during tutor song exposure. On maturation, treated birds produced poor copies of tutor song, whereas controls copied the tutor song effectively. Thus the foundation of normal song learning, the formation of a sensory memory of tutor song, requires a conserved molecular pathway in a brain area that is distinct from the circuit for song motor control.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Experimental timeline.
Figure 2: Quantitative song analysis results.
Figure 3: Auditory lobule cannula placements and zenk in situ hybridization.
Figure 4: Plots of song similarity scores and position of cannula tips.
Figure 5: Test of U0126 effects on song discrimination.


  1. 1

    Konishi, M. The role of auditory feedback in the control of vocalization in the white-crowned sparrow. Z. Tierpsychol. 22, 770–783 (1965).

  2. 2

    Nottebohm, F. & Arnold, A.P. Sexual dimorphism in vocal control areas of the songbird brain. Science 194, 211–213 (1976).

  3. 3

    Doupe, A.J., Solis, M.M., Kimpo, R. & Boettiger, C.A. Cellular, circuit and synaptic mechanisms in song learning. Ann. NY Acad. Sci. 1016, 495–523 (2004).

  4. 4

    Fee, M.S., Kozhevnikov, A.A. & Hahnloser, R.H. Neural mechanisms of vocal sequence generation in the songbird. Ann. NY Acad. Sci. 1016, 153–170 (2004).

  5. 5

    Cheng, H.Y. & Clayton, D.F. Activation and habituation of extracellular signal–regulated kinase phosphorylation in zebra finch auditory forebrain during song presentation. J. Neurosci. 24, 7503–7513 (2004).

  6. 6

    Chew, S.J., Mello, C., Nottebohm, F., Jarvis, E. & Vicario, D.S. Decrements in auditory responses to a repeated conspecific song are long-lasting and require two periods of protein synthesis in the songbird forebrain. Proc. Natl. Acad. Sci. USA 92, 3406–3410 (1995).

  7. 7

    Mello, C., Nottebohm, F. & Clayton, D. Repeated exposure to one song leads to a rapid and persistent decline in an immediate early gene's response to that song in zebra finch telencephalon. J. Neurosci. 15, 6919–6925 (1995).

  8. 8

    Mello, C.V., Vicario, D.S. & Clayton, D.F. Song presentation induces gene expression in the songbird forebrain. Proc. Natl. Acad. Sci. USA 89, 6818–6822 (1992).

  9. 9

    Stripling, R., Volman, S.F. & Clayton, D.F. Response modulation in the zebra finch neostriatum: relationship to nuclear gene regulation. J. Neurosci. 17, 3883–3893 (1997).

  10. 10

    Bolhuis, J.J., Zijlstra, G.G., Boer-Visser, A.M. & Van Der Zee, E.A. Localized neuronal activation in the zebra finch brain is related to the strength of song learning. Proc. Natl. Acad. Sci. USA 97, 2282–2285 (2000).

  11. 11

    Bolhuis, J.J., Hetebrij, E., Boer-Visser, A.M., De Groot, J.H. & Zijlstra, G.G. Localized immediate early gene expression related to the strength of song learning in socially reared zebra finches. Eur. J. Neurosci. 13, 2165–2170 (2001).

  12. 12

    Phan, M.L., Pytte, C.L. & Vicario, D.S. Early auditory experience generates long-lasting memories that may subserve vocal learning in songbirds. Proc. Natl. Acad. Sci. USA 103, 1088–1093 (2006).

  13. 13

    Terpstra, N.J., Bolhuis, J.J. & Boer-Visser, A.M. An analysis of the neural representation of birdsong memory. J. Neurosci. 24, 4971–4977 (2004).

  14. 14

    Bozon, B. et al. MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Phil. Trans. R. Soc. Lond. B 358, 805–814 (2003).

  15. 15

    Davis, S., Vanhoutte, P., Pages, C., Caboche, J. & Laroche, S. The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J. Neurosci. 20, 4563–4572 (2000).

  16. 16

    Favata, M.F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).

  17. 17

    Sweatt, J.D. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr. Opin. Neurobiol. 14, 311–317 (2004).

  18. 18

    Jin, H. & Clayton, D.F. Localized changes in immediate-early gene regulation during sensory and motor learning in zebra finches. Neuron 19, 1049–1059 (1997).

  19. 19

    Sturdy, C.B., Phillmore, L.S., Sartor, J.J. & Weisman, R.G. Reduced social contact causes auditory perceptual deficits in zebra finches, Taeniopygia guttata. Anim. Behav. 62, 1207–1218 (2001).

  20. 20

    Roper, A. & Zann, R. The onset of song learning and song tutor selection in fledgling zebra finches. Ethology 112, 458–470 (2006).

  21. 21

    Eales, L.A. Song learning in female-raised zebra finches: another look at the sensitive phase. Anim. Behav. 35, 1356–1365 (1987).

  22. 22

    Tchernichovski, O., Mitra, P.P., Lints, T. & Nottebohm, F. Dynamics of the vocal imitation process: how a zebra finch learns its song. Science 291, 2564–2569 (2001).

  23. 23

    Martin, K.C. et al. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 18, 899–912 (1997).

  24. 24

    Apergis-Schoute, A.M., Debiec, J., Doyere, V., LeDoux, J.E. & Schafe, G.E. Auditory fear conditioning and long-term potentiation in the lateral amygdala require ERK/MAP kinase signaling in the auditory thalamus: a role for presynaptic plasticity in the fear system. J. Neurosci. 25, 5730–5739 (2005).

  25. 25

    Tchernichovski, O., Nottebohm, F., Ho, C.E., Pesaran, B. & Mitra, P.P. A procedure for an automated measurement of song similarity. Anim. Behav. 59, 1167–1176 (2000).

  26. 26

    Basham, M.E., Nordeen, E.J. & Nordeen, K.W. Blockade of NMDA receptors in the anterior forebrain impairs sensory acquisition in the zebra finch (Poephila guttata). Neurobiol. Learn. Mem. 66, 295–304 (1996).

  27. 27

    Bolhuis, J.J. & Gahr, M. Neural mechanisms of birdsong memory. Nat. Rev. Neurosci. 7, 347–357 (2006).

  28. 28

    Cynx, J. & Nottebohm, F. Role of gender, season and familiarity in discrimination of conspecific song by zebra finches (Taeniopygia guttata). Proc. Natl. Acad. Sci. USA 89, 1368–1371 (1992).

  29. 29

    Scharff, C., Nottebohm, F. & Cynx, J. Conspecific and heterospecific song discrimination in male zebra finches with lesions in the anterior forebrain pathway. J. Neurobiol. 36, 81–90 (1998).

  30. 30

    Nottebohm, F., Stokes, T.M. & Leonard, C.M. Central control of song in the canary, Serinus canarius. J. Comp. Neurol. 165, 457–486 (1976).

  31. 31

    Doupe, A.J. & Kuhl, P.K. Birdsong and human speech: common themes and mechanisms. Annu. Rev. Neurosci. 22, 567–631 (1999).

  32. 32

    Olveczky, B.P., Andalman, A.S. & Fee, M.S. Vocal experimentation in the juvenile songbird requires a basal ganglia circuit. PLoS Biol. 3, e153 (2005).

  33. 33

    Bottjer, S.W., Miesner, E.A. & Arnold, A.P. Forebrain lesions disrupt development but not maintenance of song in passerine birds. Science 224, 901–903 (1984).

  34. 34

    Scharff, C. & Nottebohm, F. A comparative study of the behavioral deficits following lesions of various parts of the zebra finch song system: implications for vocal learning. J. Neurosci. 11, 2896–2913 (1991).

  35. 35

    Haesler, S. et al. Incomplete and inaccurate vocal imitation after knockdown of FoxP2 in songbird basal ganglia nucleus area X. PLoS Biol. 5, e321 (2007).

  36. 36

    Adret, P. In search of the song template. Ann. NY Acad. Sci. 1016, 303–324 (2004).

  37. 37

    Kruse, A.A., Stripling, R. & Clayton, D.F. Context-specific habituation of the zenk gene response to song in adult zebra finches. Neurobiol. Learn. Mem. 82, 99–108 (2004).

  38. 38

    Vates, G.E., Broome, B.M., Mello, C.V. & Nottebohm, F. Auditory pathways of caudal telencephalon and their relation to the song system of adult male zebra finches. J. Comp. Neurol. 366, 613–642 (1996).

  39. 39

    Terpstra, N.J., Bolhuis, J.J., Riebel, K., van der Burg, J.M. & Boer-Visser, A.M. Localized brain activation specific to auditory memory in a female songbird. J. Comp. Neurol. 494, 784–791 (2006).

  40. 40

    Kim, J.J., Song, E.Y. & Kosten, T.A. Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9, 1–11 (2006).

  41. 41

    Sauro, M.D., Jorgensen, R.S. & Pedlow, C.T. Stress, glucocorticoids and memory: a meta-analytic review. Stress 6, 235–245 (2003).

  42. 42

    Park, K.H. & Clayton, D.F. Influence of restraint and acute isolation on the selectivity of the adult zebra finch zenk gene response to acoustic stimuli. Behav. Brain Res. 136, 185–191 (2002).

  43. 43

    Huesmann, G.R. & Clayton, D.F. Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 52, 1061–1072 (2006).

  44. 44

    Gahr, M. Neural song control system of hummingbirds: comparison to swifts, vocal learning (songbirds) and nonlearning (Suboscines) passerines, and vocal learning (budgerigars) and nonlearning (dove, owl, gull, quail, chicken) nonpasserines. J. Comp. Neurol. 426, 182–196 (2000).

  45. 45

    Jarvis, E.D. & Nottebohm, F. Motor-driven gene expression. Proc. Natl. Acad. Sci. USA 94, 4097–4102 (1997).

  46. 46

    Hessler, N.A. & Doupe, A.J. Singing-related neural activity in a dorsal forebrain-basal ganglia circuit of adult zebra finches. J. Neurosci. 19, 10461–10481 (1999).

  47. 47

    Kozhevnikov, A.A. & Fee, M.S. Singing-related activity of identified HVC neurons in the zebra finch. J. Neurophysiol. 97, 4271–4283 (2007).

  48. 48

    Kao, M.H., Doupe, A.J. & Brainard, M.S. Contributions of an avian basal ganglia-forebrain circuit to real-time modulation of song. Nature 433, 638–643 (2005).

  49. 49

    Leonardo, A. Experimental test of the birdsong error-correction model. Proc. Natl. Acad. Sci. USA 101, 16935–16940 (2004).

Download references


We thank O. Tchernichovski for consultation on experimental design and song analysis, C.D. Meliza for advice on operant training hardware and procedures, R. Stripling for Labview programming expertise, J. Lee for Matlab assistance and A. Feng, K. Christie and M. Monfils for consultations and technical support for the electrophysiology experiment. We also thank G. Robinson, T. Small and K. Replogle for manuscript comments. This work was supported by an Institute for Genomic Biology Postdoctoral Fellowship, a US National Institute on Deafness and Other Communication Disorders Sensory Neuroscience Postdoctoral Training Grant, a US National Institute of Neurological Disorders and Stroke Postdoctoral National Research Service Award (S.E.L.) and a US National Institutes of Health RO1 grant (NS045264, D.F.C.).

Author information

S.E.L. and D.F.C. designed the experiments, S.E.L. acquired and analyzed the data, and S.E.L. and D.F.C. wrote the manuscript.

Correspondence to Sarah E London or David F Clayton.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Table 1 and Methods (PDF 567 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading