Abstract

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH+) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH+ neurons project more profusely than ventral tegmental area TH+ neurons to the hippocampus, optogenetic activation of locus coeruleus TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.

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Acknowledgements

We thank M. Evans for Th-Cre mice; H. Rowe and D. Tse for pilot studies; M. Lo, H-C. Tsai and C. Ramakrishnan for optogenetics training; UNC Viral Cores for producing AAVs; J. Cala, R. Fitzpatrick, J. Tulloch and T. Thai for technical support; R. Watson for animal care; N. Uchida and J. Cohen for assistance with optogenetic identification of TH+ neurons; P. Pedarzani, S. Canals, L. Genzel, M. Kroes, J. Lisman, D. Manahan-Vaughan, M. Munoz, T. Spires-Jones, S.-H. Wang, O. Eschenko and E. Wood for scientific discussion. The study was funded by the European Research Council (G.F., R.G.M.M.: ERC-2010-AdG-268800-NEUROSCHEMA), UK Medical Research Council (A.J.D., R.G.M.M.), the European Commission’s 7th Framework 2011 ICT Programme for Future Emerging Technologies (A.J.D., R.G.M.M.: 600725-GRIDMAP), Department Veterans Affairs, National Institutes of Health grant 5R01MH080297 (R.W.G.), and NIDA-T32-DA7290 Basic Science Training Program in Drug Abuse (principal investigator A. Eisch (A.S.)). The Instituto de Neurociencias at Alicante is ‘Centre of Excellence Severo Ochoa’.

Author information

Author notes

    • Tomonori Takeuchi
    • , Adrian J. Duszkiewicz
    •  & Alex Sonneborn

    These authors contributed equally to this work.

Affiliations

  1. Centre for Cognitive and Neural Systems, Edinburgh Neuroscience, The University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK

    • Tomonori Takeuchi
    • , Adrian J. Duszkiewicz
    • , Patrick A. Spooner
    •  & Richard G. M. Morris
  2. University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA

    • Alex Sonneborn
    • , Caroline C. Smith
    •  & Robert W. Greene
  3. Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, 060-8638, Japan.

    • Miwako Yamasaki
    •  & Masahiko Watanabe
  4. Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, 6525 EZ, The Netherlands.

    • Guillén Fernández
  5. Departments of Psychiatry and Behavioral Sciences and of Bioengineering, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth
  6. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, 305-8575, Japan.

    • Robert W. Greene
  7. Instituto de Neurociencias, CSIC-UMH, Alicante, 03550, Spain

    • Richard G. M. Morris

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Contributions

T.T. and A.J.D. designed with R.G.M.M. and conducted and analysed the behavioural, anatomical and in vivo electrophysiological experiments. T.T. and M.Y. designed with M.W. and conducted the tract-tracing; M.Y. analysed the data. A.S. and C.C.S. designed with R.W.G. and conducted the ex vivo electrophysiology. P.A.S. and A.J.D. constructed behavioural apparatus and optogenetic stimulation equipment. R.W.G., G.F. and R.G.M.M. secured the funding. K.D. offered advice and training to T.T. The manuscript was written by T.T., A.J.D., R.W.G. and R.G.M.M. All authors discussed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Robert W. Greene or Richard G. M. Morris.

Reviewer Information Nature thanks S. Thompson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature19325

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