Opposite effects of fear conditioning and extinction on dendritic spine remodelling (original) (raw)

Nature volume 483, pages 87–91 (2012)Cite this article

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Abstract

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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Acknowledgements

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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Authors and Affiliations

  1. Department of Physiology and Neuroscience, Molecular Neurobiology Program, Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA,
    Cora Sau Wan Lai & Wen-Biao Gan
  2. Departments of Psychiatry and Pharmacology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA,
    Thomas F. Franke

Authors

  1. Cora Sau Wan Lai
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  2. Thomas F. Franke
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  3. Wen-Biao Gan
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Contributions

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.

Corresponding author

Correspondence toWen-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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Editorial Summary

Rewiring the memory circuits

Learning and memory are thought to involve physical and functional changes to neuronal connections, but relatively little is known about structural changes to behaviour-relevant circuits. Two new studies highlight some of the physical alterations and mechanisms that may underlie learning and neural plasticity. Lai et al. analysed neurons participating in fear circuits: they found that fear learning induced a loss of dendritic spines, and that extinction of the fear caused a regrowth of spines in the same areas. Fu et al. reveal that repetitive activation of specific circuitry during motor learning can induce formation of new clusters of dendritic spines, which remain throughout prolonged learning sessions.