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Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus

Nature Neuroscience volume 10, pages 896–902 (2007)Cite this article

Abstract

Serotonin receptor 1A knockout (Htr1aKO) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1aKO mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type–specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1aKO mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli.

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Figure 1: Increased response to partially conditioned cues in Htr1aKO mice.
Figure 2: Transgenic lines expressing Htr1a in the CeA and DG.
Figure 3: Electrophysiological characterization of Htr1aCeA line.
Figure 4: Electrophysiological characterization of Htr1aDG line.
Figure 5: Suppression of conditioned responses by inhibition of neurons in the CeA and DG.

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Acknowledgements

We thank V. Carola, J. Rientjes, T. Ferreira, S. Santanelli, F. Zonfrillo and the members of the EMBL Transgenic Facility for expert help. We are grateful to F. Crestani for helpful suggestions on the ambiguous-cue fear-conditioning protocol, A. Akanwa for doing the immunohistochemistry on brain slices, and K. Ploessl and H. Kung for the gift of 125I-MPPI. This work was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (C.G.), a grant from the Fritz Thyssen Stiftung (C.G.), funds from the EMBL Ph.D. Programme (T.T. and L.L.I.), and grants from the US National Institutes of Health MH048125 and MH07540407 (S.G.B.).

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Authors and Affiliations

  1. European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, Monterotondo, 00015, Italy

    Theodoros Tsetsenis, Luisa Lo Iacono & Cornelius Gross

  2. Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, 19104, Pennsylvania, USA

    Xiao-Hong Ma & Sheryl G Beck

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Contributions

T.T. designed, executed and analyzed all genetic, histological and behavioral experiments. Electrophysiological experiments were designed, supervised and interpreted by S.G.B. and carried out by X.-H.M. L.L.I. carried out the chronic pharmacological treatment procedure. C.G. conceived of the experiments, oversaw their execution and interpretation and wrote the manuscript with input from T.T. and S.G.B.

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Correspondence to Cornelius Gross.

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Supplementary information

Supplementary Fig. 1

Increased response to partially conditioned cues in Htr1aKO mice persists at lower shock intensity. (PDF 44 kb)

Supplementary Fig. 2

Full rostral-caudal analysis of Htr1a expression in Htr1aCeA and Htr1aDG lines. (PDF 1425 kb)

Supplementary Fig. 3

Quantification of Htr1a expression in Htr1aCeA and Htr1aDG lines. (PDF 41 kb)

Supplementary Table 1

Electrophysiological characteristics of type-I and type-II neurons from the CeA. (PDF 120 kb)

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Tsetsenis, T., Ma, XH., Lo Iacono, L. et al. Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nat Neurosci 10, 896–902 (2007). https://doi.org/10.1038/nn1919

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