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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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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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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DOI: https://doi.org/10.1038/nature10792
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