Abstract
Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.
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Acknowledgements
We thank all members of the Lüthi laboratory for discussions and comments. We thank B. Kampa and T. Oertner for advice on two-photon imaging, R. Friedrich and J. Gründemann for comments on the manuscript, P. Argast, J. Lüdke and C. Müller for excellent technical assistance, H. Zielinska for preparation of artwork and S. Arber, Y. Yanagawa and K. Deisseroth for generously sharing materials. This work was supported by grants from the Swiss National Science Foundation (J.J.L. Ambizione; A.L.), the National Competence Center in Research (NCCR) of the Swiss Confederation on the synaptic basis of mental disorders, the French National Research Agency (C.H., ANR-2010-BLAN-1442-01), a Marie-Curie fellowship (J.J.L.), a Schering Foundation fellowship (S.B.E.W.), a Fonds AXA pour la Recherche fellowship (J.C.), the Aquitaine Regional Council (C.H.) and the Novartis Research Foundation.
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J.J.L. initiated the project and performed most experiments and data analyses. S.B.E.W. established optogenetic manipulation. S.B.E.W. and P.T. helped with optogenetic experiments. E.M.M.M. performed and analysed in vitro experiments. P.T. performed and analysed in vivo pharmacology. J.C. and C.H. performed and analysed single-unit recordings. 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.
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This file contains Supplementary Text relating to figures 1,2, 4 and 5 in the main paper, Supplementary Figures 1-17 with legends and additional references. (PDF 4133 kb)
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Letzkus, J., Wolff, S., Meyer, E. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480, 331–335 (2011). https://doi.org/10.1038/nature10674
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DOI: https://doi.org/10.1038/nature10674
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