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Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice

Nature Neuroscience volume 15, pages 308–314 (2012)Cite this article

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Abstract

The mediodorsal thalamic nucleus has been implicated in the control of memory processes. However, the underlying neural mechanism remains unclear. Here we provide evidence for bidirectional modulation of fear extinction by the mediodorsal thalamic nucleus. Mice with a knockout or mediodorsal thalamic nucleus–specific knockdown of phospholipase C β4 exhibited impaired fear extinction. Mutant mediodorsal thalamic nucleus neurons in slices showed enhanced burst firing accompanied by increased T-type Ca2+ currents; blocking of T channels in vivo rescued the fear extinction. Tetrode recordings in freely moving mice revealed that, during extinction, the single-spike (tonic) frequency of mediodorsal thalamic nucleus neurons increased in wild-type mice, but was static in mutant mice. Furthermore, tonic-evoking microstimulations of the mediodorsal thalamic nucleus, contemporaneous with the extinction tones, rescued fear extinction in mutant mice and facilitated it in wild-type mice. In contrast, burst-evoking microstimulation suppressed extinction in wild-type mice, mimicking the mutation. These results suggest that the firing mode of the mediodorsal thalamic nucleus is critical for the modulation of fear extinction.

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Figure 1: Defective extinction of auditory-conditioned fear memory in Plcb4−/− mice.
Figure 2: Blockade of the mediodorsal thalamic mGluR1-PLCβ4 pathway inhibits fear extinction.
Figure 3: Stronger low-threshold burst firing and enhanced LVCCs in mediodorsal thalamic nucleus neurons of Plcb4−/− mice.
Figure 4: Accelerating effect of an intra–mediodorsal thalamic nucleus infusion of a T-type Ca2+ channel blocker on fear extinction learning, but not on consolidation of extinction.
Figure 5: Changes in conditioned stimulus–evoked burst and tonic firing patterns of mediodorsal thalamic nucleus neurons in wild-type and Plcb4−/− mice during extinction learning.
Figure 6: Opposite effects of mediodorsal thalamic nucleus electric stimulation, mimicking dual firing, on fear extinction learning.

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Change history

  • 08 January 2012

    In the version of this article initially published online, Plcb4 was misspelled Plcb44 in two places. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank J. Park for assistance with animal care and I. Hong for behavioral tests in the beginning of this work. This work was supported by a grant from the National Honor Scientist Program of Korea and a grant from the 21C Frontier Proteomics Program of the Ministry of Education, Science and Technology, Korea.

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Authors and Affiliations

  1. Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea

    Sukchan Lee, Touqeer Ahmed, Soojung Lee, Huisu Kim, Jeiwon Cho & Hee-Sup Shin

  2. Department of Physiology, Seoul National University College of Medicine, Seoul, Korea

    Sukchan Lee & Sang Jeong Kim

  3. Department of Neuroscience, University of Science and Technology, Daejeon, Korea

    Huisu Kim & Hee-Sup Shin

  4. School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea

    Sukwoo Choi

  5. Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan-Si, Korea

    Duk-Soo Kim

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Contributions

Sukchan Lee and H.-S.S. designed the experiments and wrote the manuscript. S.J.K. helped write the manuscript. S.C. was involved in the design of the initial behavioral experiments. Sukchan Lee and H.K. performed all surgery, microinjection and microstimulation, and analyzed the data. Sukchan Lee, T.A. and J.C. performed in vivo electrophysiology. Soojung Lee performed slice electrophysiology. D.-S.K. was responsible for immunostaining. All of the authors discussed the results and commented on the manuscript.

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Correspondence to Hee-Sup Shin.

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Lee, S., Ahmed, T., Lee, S. et al. Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice. Nat Neurosci 15, 308–314 (2012). https://doi.org/10.1038/nn.2999

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