Article | Published:

Amygdala interneuron subtypes control fear learning through disinhibition

Nature volume 509, pages 453458 (22 May 2014) | Download Citation

Abstract

Learning is mediated by experience-dependent plasticity in neuronal circuits. Activity in neuronal circuits is tightly regulated by different subtypes of inhibitory interneurons, yet their role in learning is poorly understood. Using a combination of in vivo single-unit recordings and optogenetic manipulations, we show that in the mouse basolateral amygdala, interneurons expressing parvalbumin (PV) and somatostatin (SOM) bidirectionally control the acquisition of fear conditioning—a simple form of associative learning—through two distinct disinhibitory mechanisms. During an auditory cue, PV+ interneurons are excited and indirectly disinhibit the dendrites of basolateral amygdala principal neurons via SOM+ interneurons, thereby enhancing auditory responses and promoting cue–shock associations. During an aversive footshock, however, both PV+ and SOM+ interneurons are inhibited, which boosts postsynaptic footshock responses and gates learning. These results demonstrate that associative learning is dynamically regulated by the stimulus-specific activation of distinct disinhibitory microcircuits through precise interactions between different subtypes of local interneurons.

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Acknowledgements

We thank all members of the Lüthi laboratory and E. Schuman for discussions and critical comments on the manuscript. We would like to thank J. Lüdke, P. Argast and P. Buchmann for technical assistance. We further thank the Facility for Imaging and Microscopy at the FMI, in particular S. Bourke and M. Kirschmann, for their assistance in image acquisition and analysis. We also thank K. Deisseroth, E. Boyden, J. Huang, R. Sprengel and S. Arber for sharing materials and mouse lines. This work was supported by the Novartis Research Foundation, by the National Center of Competences in Research: ‘SYNAPSY — The Synaptic Bases of Mental Diseases’ (financed by the Swiss National Science Foundation) as well as by a SNSF core grant to A.L. S.B.E.W. is supported by a Schering Foundation Fellowship. J.J.L. is supported by a Swiss National Science Foundation Ambizione Fellowship. J.G. and G.A.J. are supported by EMBO Long-Term Fellowships and Marie Curie Action Fellowships.

Author information

Author notes

    • Steffen B. E. Wolff
    • , Jan Gründemann
    • , Johannes J. Letzkus
    •  & Andreas Lüthi

    These authors contributed equally to this work.

    • Johannes J. Letzkus

    Present address: Max-Planck Institute for Brain Research, 60438 Frankfurt, Germany.

Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

    • Steffen B. E. Wolff
    • , Jan Gründemann
    • , Philip Tovote
    • , Sabine Krabbe
    • , Gilad A. Jacobson
    • , Christian Müller
    • , Rainer W. Friedrich
    • , Johannes J. Letzkus
    •  & Andreas Lüthi
  2. University of Basel, 4000 Basel, Switzerland

    • Steffen B. E. Wolff
  3. INSERM U862, Neurocentre Magendie, 146 rue Leo Saignat, 33077 Bordeaux, France

    • Cyril Herry
  4. Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany

    • Ingrid Ehrlich

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Contributions

S.B.E.W. initiated the project, performed most experiments and data analysis, and wrote the manuscript. J.G. performed and analysed in vitro experiments and immunohistochemistry. P.T. performed and analysed immunohistochemistry. S.K. performed in vitro experiments and analysed subcellular targeting experiments. G.A.J. and R.W.F. performed and helped with data analysis. C.M. provided technical assistance. C.H. and I.E. helped to establish optogenetic manipulations and single-unit recordings. S.B.E.W., J.J.L. and A.L. conceived the project and wrote the manuscript. All authors contributed to the experimental design and interpretation, and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Johannes J. Letzkus or Andreas Lüthi.

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DOI

https://doi.org/10.1038/nature13258

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