Experience-dependent modification of a central amygdala fear circuit


The amygdala is essential for fear learning and expression. The central amygdala (CeA), once viewed as a passive relay between the amygdala complex and downstream fear effectors, has emerged as an active participant in fear conditioning. However, the mechanism by which CeA contributes to the learning and expression of fear is unclear. We found that fear conditioning in mice induced robust plasticity of excitatory synapses onto inhibitory neurons in the lateral subdivision of the CeA (CeL). This experience-dependent plasticity was cell specific, bidirectional and expressed presynaptically by inputs from the lateral amygdala. In particular, preventing synaptic potentiation onto somatostatin-positive neurons impaired fear memory formation. Furthermore, activation of these neurons was necessary for fear memory recall and was sufficient to drive fear responses. Our findings support a model in which fear conditioning–induced synaptic modifications in CeL favor the activation of somatostatin-positive neurons, which inhibit CeL output, thereby disinhibiting the medial subdivision of CeA and releasing fear expression.

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Figure 1: Fear conditioning induces modifications of excitatory synapses onto neurons in CeL.
Figure 2: The fear conditioning–induced synaptic modifications in CeL are expressed presynaptically at the lateral amygdala–CeL pathway.
Figure 3: Auditory thalamus does not drive excitatory synaptic transmission onto CeL neurons.
Figure 4: Synaptic potentiation onto SOM+ neurons in CeL is required for the formation of fear memory.
Figure 5: SOM+ CeL neurons do not project to CeM.
Figure 6: SOM+ CeL neurons do not inhibit CeM neurons that project to PAG.
Figure 7: SOM+ neurons in CeL control the expression of fear.


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We thank R.H. Paik for expert technical assistance, K. Deisseroth and M. Mirrione for the initial help with optogenetic methods, M. Luo (National Institute of Biological Sciences, Beijing) and S.H. Shi (Memorial Sloan-Kettering Cancer Center) for the AAV-DIO-hM4Di-mCherry construct, W. Wei for help with the focal optogenetic stimulation, A. Zador (Cold Spring Harbor Laboratory) for sharing the AAV-DIO-ChR2(H134R)-YFP and AAV-DIO-Arch-GFP viruses, A. Reid (Cold Spring Harbor Laboratory) for sharing the Ai32 mice, and K. Pradhan for advice on statistic analysis. We thank S. Shea, L. Van Aelst and R. Malinow for critical reading of the manuscript, and members of the Li laboratory for discussions. This study was supported by the US National Institutes of Health (5R01MH091903-03 to B.L. and 5U01MH078844-05 to Z.J.H.), the Dana Foundation (B.L.) and the National Alliance for Research on Schizophrenia and Depression (B.L. and Z.J.H.).

Author information




H.L. and M.A.P. performed the experiments. H.L., M.A.P. and B.L. analyzed the data. H.T. and Z.J.H. provided critical reagents and advice. C.D.K. developed the MatLab programs for statistical (bootstrap) and behavioral analysis. H.L., M.A.P. and B.L. designed the study. B.L. wrote the manuscript.

Corresponding author

Correspondence to Bo Li.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 37348 kb)

Supplementary Movie 1

ChR2 activation of SOM+ neurons in CeL induces freezing responses in a naive mouse. Movie (1x) shows the behavior of one of the "ChR2" mice described in Figure 7c. The precise timing of the two 20-s blue light pulses delivered bilaterally into CeL (for the activation of ChR2) is indicated in the lower right corner (Light ON, twice). Freezing responses were reversibly induced upon the delivery of light pulses. (MOV 24103 kb)

Supplementary Movie 2

Arch inhibition of SOM+ neurons in CeL attenuates conditioned freezing responses in a fear-conditioned mouse. Movie (1×) shows the behavior of one of the Arch mice described in Figure 7e. A two-trial fear memory testing session 24 h after fear conditioning is shown. In the first trial a 20-s tone (CS) was presented during the delivery of a green light bilaterally into CeL (for the activation of Arch). The green light can be seen as a bright spot on the mouse's head. In the second trial the CS was presented in the absence of the green light. The timing of each trial is indicated in the lower right corner. A house light was kept on throughout the testing sessions to mask the green laser light. (MOV 41833 kb)

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Li, H., Penzo, M., Taniguchi, H. et al. Experience-dependent modification of a central amygdala fear circuit. Nat Neurosci 16, 332–339 (2013). https://doi.org/10.1038/nn.3322

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