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Genetic dissection of an amygdala microcircuit that gates conditioned fear

Haubensak, Wulf and Kunwar, Prabhat S. and Cai, Haijiang and Ciocchi, Stephane and Wall, Nicholas R. and Ponnusamy, Ravikumar and Biag, Jonathan and Dong, Hong-Wei and Deisseroth, Karl and Callaway, Edward M. and Fanselow, Michael S. and Lüthi, Andreas and Anderson, David J. (2010) Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature, 468 (7321). pp. 270-276. ISSN 0028-0836. PMCID PMC3597095. doi:10.1038/nature09553.

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The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ^+ neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ^− neurons in CEl. Electrical silencing of PKC-δ^+ neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called Cel_(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.

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Fanselow, Michael S.0000-0002-3850-5966
Anderson, David J.0000-0001-6175-3872
Additional Information:© 2010 Macmillan Publishers Limited. Received 23 February 2010; Accepted 06 October 2010; Published online 10 November 2010. We thank N. Heinz and X. Gong for generating BAC transgenic mice; C. Saper for providing the Cre-dependent hrGFP AAV construct; C. Xiao for training in slice electrophysiology and preliminary experiments; H. Lester for advice on the GluCl system; L. van Tright for performing in situ hybridizations; W. Lerchner for providing a CAG-driven GluClb construct; A. Chang for help with behavioural scoring; M. Martinez for tail genotyping; G. Mosconi for laboratory management; and J. Alex, R. Bayon and R. Sauza for animal care. This work was supported by NIH grant 1 R01 MH085082-01A1 and by funds from the Caltech ‘Conscious Mouse’ project. W.H. was supported by a fellowship of the Human Frontier Science Program and P.S.K. by the Jane Coffin Childs Memorial Fund for Medical Research. S.C. and A.L. were supported by the Novartis Research Foundation. D.J.A. is an Investigator of the Howard Hughes Medical Institute. Author Contributions: W.H. initiated the project, generated BAC constructs, designed experiments, performed anatomical, viral injections and behavioural experiments, and wrote the manuscript. P.S.K. contributed to experimental design, performed viral injections, behavioural experiments, data analysis and interpretation. H.C. contributed to experimental design and performed viral injections and slice electrophysiology experiments, data analysis and interpretation. S.C. and A.L. designed, performed and interpreted in vivo recording experiments (Fig. 5). N.R.W. and E.M.C. performed rabies virus injection experiments. R.P. performed supplementary behavioural experiments and M.S.F. contributed to their interpretation and to statistical analysis. J.B. and H.-W.D. performed supplementary stereotaxic viral injection experiments. K.D. provided Cre-dependent ChR2 constructs and advice. D.J.A. conceived the project, contributed to experimental design and interpretation and wrote the manuscript. P.S.K., H.C. and S.C. contributed equally. All authors discussed the results and commented on the manuscript.
Funding AgencyGrant Number
NIH1 R01 MH085082-01A1
Human Frontier Science ProgramUNSPECIFIED
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
Novartis Research FoundationUNSPECIFIED
Subject Keywords:Neuroscience
Issue or Number:7321
PubMed Central ID:PMC3597095
Record Number:CaltechAUTHORS:20101206-112525797
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:21186
Deposited By: Tony Diaz
Deposited On:06 Dec 2010 20:51
Last Modified:09 Nov 2021 00:06

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