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Modular organization of the brainstem noradrenaline system coordinates opposing learning states

Nature Neuroscience volume 20, pages 16021611 (2017) | Download Citation

Abstract

Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.

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Acknowledgements

We thank M. Iwasaki, A. Umetsu, K. Mori and A. Krejcirikova for excellent technical assistance and H. Hamanaka for setting up rabies virus production in the lab. We thank C. Yokoyama, A. Luthi, H. Schiff, T. Shimogori, S. Fujisawa, T. McHugh, A. Benucci and members of the Johansen lab for comments on earlier versions of the manuscript. We also thank J. Kleinschmidt (German Cancer Research Center) for his gift of the AAV helper vectors and the RIKEN Research Resources Center for help with viral titering. This work was supported by RIKEN SPRP (A.U. and B.Z.T.), KAKENHI 16H01291, 15H04264, 15H01301 (J.P.J.), 16K21620 (B.Z.T.), 26750380, 16H05928 (A.U.)) and the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology (11041047, J.P.J.).

Author information

Author notes

    • Akira Uematsu
    •  & Bao Zhen Tan

    These authors contributed equally to this work.

Affiliations

  1. RIKEN Brain Science Institute, Laboratory for Neural Circuitry of Memory, Wako, Japan.

    • Akira Uematsu
    • , Bao Zhen Tan
    • , Edgar A Ycu
    • , Jessica Sulkes Cuevas
    • , Jenny Koivumaa
    •  & Joshua P Johansen
  2. Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan.

    • Jessica Sulkes Cuevas
    •  & Joshua P Johansen
  3. Institut de Génétique Moléculaire de Montpellier, Montpellier, France.

    • Felix Junyent
    •  & Eric J Kremer
  4. Princeton Neuroscience Institute and Department of Psychology, Princeton, New Jersey, USA.

    • Ilana B Witten
  5. Bioengineering Department, Stanford University, Stanford, California, USA.

    • Karl Deisseroth
  6. CNC Program, Stanford University, Stanford, California, USA.

    • Karl Deisseroth
  7. Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.

    • Karl Deisseroth
  8. RIKEN BSI-Kao Collaboration Center, Wako, Japan.

    • Joshua P Johansen

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Contributions

A.U., B.Z.T. and J.P.J. designed the experiments and wrote up the manuscript. A.U., B.Z.T., E.A.Y., J.S.C. and J.K. carried out the experiments. A.U., B.Z.T. and J.P.J. analyzed the results. F.J. and E.J.K. supplied viral reagents before publication and expert advice on their use. I.B.W. and K.D. supplied viral reagents and transgenic animals before publication as well as expert advice on their use.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Akira Uematsu or Joshua P Johansen.

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DOI

https://doi.org/10.1038/nn.4642

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