Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Encoding of conditioned fear in central amygdala inhibitory circuits

Nature volume 468, pages 277–282 (2010)Cite this article

Subjects

Abstract

The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Differential role of CEl and CEm in fear expression and acquisition.
Figure 2: Fear conditioning induces cell-type-specific plasticity in CEl inhibitory circuits.
Figure 3: Fear conditioning induces disinhibition of CEm output neurons.
Figure 4: Cell-type-specific plasticity of tonic activity regulates fear generalization.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Davis, M. The role of the amygdala in conditioned and unconditioned fear and anxiety. In The Amygdala (ed., Aggleton, J. P.) 213–288 (Oxford Univ. Press, 2000)

    Google Scholar 

  3. Maren, S. & Quirk, G. J. Neuronal signalling of fear memory. Nature Rev. Neurosci. 5, 844–852 (2004)

    Article  CAS  Google Scholar 

  4. Sigurdsson, T., Doyère, V., Cain, C. K. & LeDoux, J. E. Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory. Neuropharmacology 52, 215–227 (2007)

    Article  CAS  Google Scholar 

  5. Sah, P., Westbrook, R. F. & Lüthi, A. Fear conditioning and long-term potentiation: what really is the connection? Ann. NY Acad. Sci. 1129, 88–95 (2008)

    Article  CAS  ADS  Google Scholar 

  6. Krettek, J. E. & Price, J. L. A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections. J. Comp. Neurol. 178, 255–279 (1978)

    Article  CAS  Google Scholar 

  7. Veening, J. G., Swanson, L. W. & Sawchenko, P. E. The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res. 303, 337–357 (1984)

    Article  CAS  Google Scholar 

  8. LeDoux, J. E., Iwata, J., Cicchetti, P. & Reis, D. J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988)

    Article  CAS  Google Scholar 

  9. Pascoe, J. P. & Kapp, B. S. Electrophysiological characteristics of amygdaloid central nucleus neurons during Pavlovian fear conditioning in the rabbit. Behav. Brain Res. 16, 117–133 (1985)

    Article  CAS  Google Scholar 

  10. Goosens, K. A. & Maren, S. Pretraining NMDA receptor blockade in the basolateral complex, but not the central nucleus, of the amygdala prevents savings of conditional fear. Behav. Neurosci. 117, 738–750 (2003)

    Article  CAS  Google Scholar 

  11. Wilensky, A. E., Schafe, G. E., Kristensen, M. P. & LeDoux, J. E. Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. J. Neurosci. 26, 12387–12396 (2006)

    Article  CAS  Google Scholar 

  12. Samson, R. D., Duvarci, S. & Paré, D. Synaptic plasticity in the central nucleus of the amygdala. Rev. Neurosci. 16, 287–302 (2005)

    Article  Google Scholar 

  13. Ehrlich, I. et al. Amygdala inhibitory circuits and the control of fear memory. Neuron 62, 757–771 (2009)

    Article  CAS  Google Scholar 

  14. Sun, N., Yi, H. & Cassell, M. D. Evidence for a GABAergic interface between cortical afferents and brainstem projection neurons in the rat central extended amygdala. J. Comp. Neurol. 340, 43–64 (1994)

    Article  CAS  Google Scholar 

  15. Cassell, M. D., Freedman, L. J. & Shi, C. The intrinsic organization of the central extended amygdala. Ann. NY Acad. Sci. 877, 217–241 (1999)

    Article  CAS  ADS  Google Scholar 

  16. Veinante, P. & Freund-Mercier, M. J. Branching patterns of central amygdaloid nucleus afferents in the rat: Single axon reconstructions. Ann. NY Acad. Sci. 985, 552–553 (2003)

    Article  ADS  Google Scholar 

  17. Huber, D., Veinante, P. & Stoop, R. Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala. Science 308, 245–248 (2005)

    Article  CAS  ADS  Google Scholar 

  18. Roberto, M., Madamba, S. G., Moore, S. D., Tallent, M. K. & Siggins, G. R. Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc. Natl Acad. Sci. USA 100, 2053–2058 (2003)

    Article  CAS  ADS  Google Scholar 

  19. Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo . J. Neurosci. 27, 14231–14238 (2007)

    Article  CAS  Google Scholar 

  20. Tang, W. et al. Faithful expression of multiple proteins via 2A-peptide self-processing: A versatile and reliable method for manipulating brain circuits. J. Neurosci. 29, 8621–8629 (2009)

    Article  CAS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  22. LeDoux, J. E., Ruggiero, D. A. & Reis, D. J. Projections to the subcortical forebrain from anatomically defined regions of the medial geniculate body in the rat. J. Comp. Neurol. 242, 182–213 (1985)

    Article  CAS  Google Scholar 

  23. Turner, B. H. & Herkenham, M. Thalamoamygdaloid projections in the rat: a test of the amygdala’s role in sensory processing. J. Comp. Neurol. 313, 295–325 (1991)

    Article  CAS  Google Scholar 

  24. Linke, R., Braune, G. & Schwegler, H. Differential projection of the posterior paralaminar thalamic nuclei to the amygdaloid complex in the rat. Exp. Brain Res. 134, 520–532 (2000)

    Article  CAS  Google Scholar 

  25. Lima, S. Q., Hromadka, T., Znamenskiy, P. & Zador, A. M. PINP: a new method of tagging neuronal populations for identification during in vivo electrophysiological recording. PLoS ONE 4, e6099 (2009)

    Article  ADS  Google Scholar 

  26. Pitkänen, A., Savander, V. & LeDoux, J. E. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci. 20, 517–523 (1997)

    Article  Google Scholar 

  27. Haubensak, W. et al. Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature doi:10.1038/nature09553 (this issue).

  28. Delaney, A. J., Crane, J. W. & Sah, P. Noradrenaline modulates transmission at a central synapse by a presynaptic mechanism. Neuron 56, 880–892 (2007)

    Article  CAS  Google Scholar 

  29. Fu, Y. & Shinnick-Gallagher, P. Two intra-amygdaloid pathways to the central amygdala exhibit different mechanisms of long-term potentiation. J. Neurophysiol. 93, 3012–3015 (2005)

    Article  CAS  Google Scholar 

  30. Lopez de Armentia, M. & Sah, P. Bidirectional synaptic plasticity at nociceptive afferents in the rat central amygdala. J. Physiol. (Lond.) 581, 961–970 (2007)

    Article  Google Scholar 

  31. Samson, R. D. & Paré, D. Activity-dependent synaptic plasticity in the central nucleus of the amygdala. J. Neurosci. 25, 1847–1855 (2005)

    Article  CAS  Google Scholar 

  32. Millhouse, O. E. The intercalated cells of the amygdala. J. Comp. Neurol. 247, 246–271 (1986)

    Article  CAS  Google Scholar 

  33. Paré, D. & Smith, Y. The intercalated cell masses project to the central and medial nuclei of the amygdala in cats. Neuroscience 57, 1077–1090 (1993)

    Article  Google Scholar 

  34. Paré, D., Quirk, G. J. & LeDoux, J. E. New vistas on amygdala networks in conditioned fear. J. Neurophysiol. 92, 1–9 (2004)

    Article  Google Scholar 

  35. Thompson, R. F. The role of the cerebral cortex in stimulus generalization. J. Comp. Physiol. Psychol. 55, 279–287 (1962)

    Article  CAS  Google Scholar 

  36. Jarrell, T. W., Gentile, C. G., Romanski, L. M., McCabe, P. M. & Schneidermann, N. Involvement of cortical and thalamic auditory regions in retention of differential bradycardia conditioning to acoustic conditioned stimuli in rabbits. Brain Res. 412, 285–294 (1987)

    Article  CAS  Google Scholar 

  37. Shaban, H. et al. Generalization of amygdala LTP and conditioned fear in the absence of presynaptic inhibition. Nature Neurosci. 9, 1028–1035 (2006)

    Article  CAS  Google Scholar 

  38. Cardinal, R. N., Parkinson, J. A., Hall, J. & Everitt, B. J. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci. Biobehav. Rev. 26, 321–352 (2002)

    Article  Google Scholar 

  39. Balleine, B. W. & Killcross, S. Parallel incentive processing: an integrated view of amygdala function. Trends Neurosci. 29, 272–279 (2006)

    Article  CAS  Google Scholar 

  40. Neugebauer, V., Galhardo, V., Maione, S. & Mackey, S. C. Forebrain pain mechanisms. Brain Res. Brain Res. Rev. 60, 226–242 (2009)

    Article  Google Scholar 

  41. Jolkkonen, E., Miettinen, R., Pikkarainen, M. & Pitkänen, A. Projections from the amygdaloid complex to the magnocellular cholinergic basal forebrain in rat. Neuroscience 111, 133–149 (2002)

    Article  CAS  Google Scholar 

  42. Gozzi, A. et al. A neural switch for active and passive fear. Neuron 67, 656–666 (2010)

    Article  CAS  Google Scholar 

  43. Wickens, J. R., Arbuthnott, G. W. & Shindou, T. Simulation of GABA function in the basal ganglia: computational models of GABAergic mechanisms in basal ganglia function. Prog. Brain Res. 160, 313–329 (2007)

    Article  CAS  Google Scholar 

  44. Nicolelis, M. A. L. et al. Chronic, multisite, multielectrode recordings in macaque monkeys. Proc. Natl Acad. Sci. USA 100, 11041–11046 (2003)

    Article  CAS  ADS  Google Scholar 

  45. Herry, C. et al. Processing of temporal unpredictability in human and animal amygdala. J. Neurosci. 27, 5958–5966 (2007)

    Article  CAS  Google Scholar 

  46. Fujisawa, S., Amarasingham, A., Harrison, M. T. & Buzsaki, G. Behavior-dependent short-term assembly dynamics in the medial prefrontal cortex. Nature Neurosci. 11, 823–833 (2008)

    Article  CAS  Google Scholar 

  47. Lang, E. J. & Paré, D. Synaptic and synaptically activated intrinsic conductances underlie inhibitory potentials in cat lateral amygdaloid projection neurons in vivo . J. Neurophysiol. 77, 353–363 (1997)

    Article  CAS  Google Scholar 

  48. Lima, S. Q., Hromadka, T., Znamenskiy, P. & Zador, A. M. PINP: a new method of tagging neuronal populations for identification during in vivo electrophysiological recording. PLoS ONE 4, e6099 (2009)

    Article  ADS  Google Scholar 

Download references

Acknowledgements

We thank all members of the Lüthi laboratory for discussions and critical comments on the manuscript. This work was supported by grants from the Austrian Science Fund (FWF), the Swiss National Science Foundation, the Schering Foundation, the European Commission (Eurospin Project, Contract HEALTH-F2-2009-241498), the Indo Swiss Joint Research Programme, the BMBF (grant 01GQ0420 to BCCN Freiburg), Neurex Interreg-IV, the Volkswagen Stiftung, the Novartis Institutes for Biomedical Research, and the Novartis Research Foundation.

Author information

Author notes

  1. Cyril Herry & Ingrid Ehrlich

    Present address: Present addresses: INSERM U862, Neurocentre Magendie, 146 Rue Léo-Saignat, 33077 Bordeaux, France (C.H.); Hertie Institute for Clinical Brain Research, 72076 Tübingen, Germany (I.E.).,

  2. Stephane Ciocchi and Cyril Herry: These authors contributed equally to this work.

Authors and Affiliations

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

    Stephane Ciocchi, Cyril Herry, François Grenier, Steffen B. E. Wolff, Johannes J. Letzkus, Ingrid Ehrlich, Michael B. Stadler, Christian Müller & Andreas Lüthi

  2. Bernstein Center for Computational Neuroscience, 79104 Freiburg, Germany ,

    Ioannis Vlachos

  3. Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany,

    Rolf Sprengel

  4. Department of Bioengineering, Stanford University, Stanford, 94305, California, USA

    Karl Deisseroth

Authors
  1. Stephane Ciocchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cyril Herry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. François Grenier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steffen B. E. Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johannes J. Letzkus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ioannis Vlachos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ingrid Ehrlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rolf Sprengel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karl Deisseroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael B. Stadler
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andreas Lüthi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.C. and C.H. initiated the project. S.C., C.H., F.G., S.B.E.W. and C.M. performed the experiments. S.C., C.H., F.G., S.B.E.W., I.V., M.B.S. and A.L. analysed the data. K.D. and R.S. provided constructs and advice. S.C., C.H., F.G., S.B.E.W., I.E. and J.J.L. contributed to the experimental design and interpretation. A.L. conceived the project, contributed to the experimental design and interpretation, analysed data and wrote the manuscript. S.C. and C.H. contributed equally. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Andreas Lüthi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Notes, an additional reference and Supplementary Figures 1-16 with legends. (PDF 8275 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ciocchi, S., Herry, C., Grenier, F. et al. Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468, 277–282 (2010). https://doi.org/10.1038/nature09559

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09559

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing