Opposite effects of fear conditioning and extinction on dendritic spine remodelling


It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories1,2,3. Although this view has gained much support from behavioural and electrophysiological studies1,2,3,4,5,6,7,8,9,10, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy11,12, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.

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Figure 1: Fear conditioning causes spine elimination.
Figure 2: Fear extinction induces spine formation.
Figure 3: Fear conditioning and extinction cause location-specific spine remodelling.
Figure 4: Extinction induces spine formation in a cue- and location-specific manner.
Figure 5: Reconditioning eliminates spines formed during extinction.


  1. 1

    Myers, K. M. & Davis, M. Mechanisms of fear extinction. Mol. Psychiatry 12, 120–150 (2007)

    CAS  Article  Google Scholar 

  2. 2

    Quirk, G. J. & Mueller, D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33, 56–72 (2008)

    Article  Google Scholar 

  3. 3

    Bouton, M. E. Context and behavioral processes in extinction. Learn. Mem. 11, 485–494 (2004)

    Article  Google Scholar 

  4. 4

    Rescorla, R. A. & Heth, C. D. Reinstatement of fear to an extinguished conditioned stimulus. J. Exp. Psychol. Anim. Behav. Process. 1, 88–96 (1975)

    CAS  Article  Google Scholar 

  5. 5

    Bouton, M. E. & King, D. A. Contextual control of the extinction of conditioned fear: tests for the associative value of the context. J. Exp. Psychol. Anim. Behav. Process. 9, 248–265 (1983)

    CAS  Article  Google Scholar 

  6. 6

    Thomas, D. R. & Sherman, L. An assessment of the role of handling cues in “spontaneous recovery” after extinction. J. Exp. Anal. Behav. 46, 305–314 (1986)

    CAS  Article  Google Scholar 

  7. 7

    Herry, C. et al. Switching on and off fear by distinct neuronal circuits. Nature 454, 600–606 (2008)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Burgos-Robles, A., Vidal-Gonzalez, I. & Quirk, G. J. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure. J. Neurosci. 29, 8474–8482 (2009)

    CAS  Article  Google Scholar 

  9. 9

    Milad, M. R. & Quirk, G. J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Tronson, N. C. et al. Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear. J. Neurosci. 29, 3387–3394 (2009)

    CAS  Article  Google Scholar 

  11. 11

    Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Yang, G., Pan, F. & Gan, W. B. Stably maintained dendritic spines are associated with lifelong memories. Nature 462, 920–924 (2009)

    ADS  CAS  Article  Google Scholar 

  13. 13

    LeDoux, J. E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000)

    CAS  Article  Google Scholar 

  14. 14

    Kim, J. H. & Richardson, R. The effect of temporary amygdala inactivation on extinction and reextinction of fear in the developing rat: unlearning as a potential mechanism for extinction early in development. J. Neurosci. 28, 1282–1290 (2008)

    CAS  Article  Google Scholar 

  15. 15

    Hong, I., Song, B., Lee, S., Kim, J. & Choi, S. Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala. Eur. J. Neurosci. 30, 2089–2099 (2009)

    Article  Google Scholar 

  16. 16

    Lin, C. H., Yeh, S. H., Lu, H. Y. & Gean, P. W. The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory. J. Neurosci. 23, 8310–8317 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Merlo, E. & Romano, A. Memory extinction entails the inhibition of the transcription factor NF-κB. PLoS ONE 3, e3687 (2008)

    ADS  Article  Google Scholar 

  18. 18

    Clem, R. L. & Huganir, R. L. Calcium-permeable AMPA receptor dynamics mediate fear memory erasure. Science 330, 1108–1112 (2010)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Denk, W., Strickler, J. H. & Webb, W. W. Two-photon laser scanning fluorescence microscopy. Science 248, 73–76 (1990)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Condé, F., Maire-Lepoivre, E., Audinat, E. & Crepel, F. Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents. J. Comp. Neurol. 352, 567–593 (1995)

    Article  Google Scholar 

  21. 21

    McDonald, A. J. Organization of amygdaloid projections to the mediodorsal thalamus and prefrontal cortex: a fluorescence retrograde transport study in the rat. J. Comp. Neurol. 262, 46–58 (1987)

    CAS  Article  Google Scholar 

  22. 22

    Sacchetti, B., Baldi, E., Lorenzini, C. A. & Bucherelli, C. Role of the neocortex in consolidation of fear conditioning memories in rats. Exp. Brain Res. 152, 323–328 (2003)

    Article  Google Scholar 

  23. 23

    Garcia, R., Vouimba, R. M., Baudry, M. & Thompson, R. F. The amygdala modulates prefrontal cortex activity relative to conditioned fear. Nature 402, 294–296 (1999)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Ziv, N. E. & Smith, S. J. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 17, 91–102 (1996)

    CAS  Article  Google Scholar 

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We thank J. LeDoux as well as all the members in the Gan laboratory for comments on the manuscript. This work was supported by National Institutes of Health grant NS047325 and the Investigator-Initiated Research Grant from the Alzheimer‘s Association (W.-B.G.), and by the National Science Foundation (#IOS-0757780), a 2008 NARSAD Independent Investigator Award and the G. Harold & Leila Y. Mathers Foundation (T.F.F.).

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C.S.W.L. and W.-B.G. designed the imaging experiments. C.S.W.L., W.-B.G. and T.F.F. designed the behavioural paradigms. C.S.W.L. performed all the experiments and data analysis. T.F.F. helped with the behavioural data analysis. W.-B.G. supervised the work. W.-B.G., C.S.W.L. and T.F.F. wrote the manuscript.

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Correspondence to Wen-Biao Gan.

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The authors declare no competing financial interests.

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Lai, C., Franke, T. & Gan, WB. Opposite effects of fear conditioning and extinction on dendritic spine remodelling. Nature 483, 87–91 (2012). https://doi.org/10.1038/nature10792

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