Article | Published:

Rabies screen reveals GPe control of cocaine-triggered plasticity

Nature volume 549, pages 345350 (21 September 2017) | Download Citation

Abstract

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.

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Acknowledgements

This study was supported by grants from the Howard Hughes Medical Institute (Hughes Collaborative Innovation Award), National Institutes of Health (R01-NS50835, PO1 DA008227, TR01-MH099647, F32-DA038913, K99-DC013059 and K99-DA041445), and the Stanford Neurosciences Institute.

Author information

Author notes

    • Timothy J. Mosca

    Present address: Department of Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Affiliations

  1. Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA

    • Kevin T. Beier
    • , Paul Hoerbelt
    • , Lin Wai Hung
    • , Boris D. Heifets
    • , Sophie Neuner
    •  & Robert C. Malenka
  2. Department of Biology, Stanford University, Stanford, California 94305, USA

    • Kevin T. Beier
    • , Katherine E. DeLoach
    • , Timothy J. Mosca
    •  & Liqun Luo
  3. Neurosciences Program, Stanford University, Stanford, California 94305, USA

    • Christina K. Kim
  4. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    • Boris D. Heifets
  5. Department of Bioengineering, Stanford University, Stanford, California 94305, USA

    • Karl Deisseroth
  6. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA

    • Karl Deisseroth
  7. Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA

    • Katherine E. DeLoach
    • , Karl Deisseroth
    •  & Liqun Luo

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Contributions

K.T.B. performed the majority of experiments and data analysis; C.K.K. assisted with fibre photometry experiments and data analysis with support from K.D; P.H. assisted with electrophysiological recordings and data analysis; L.W.H. performed surgeries for ChR2 stimulation and Fos counting; B.D.H. assisted with terminal inhibition experiments; T.J.M. assisted with assay design for puncta quantification; K.E.D. and S.N. provided technical support; K.T.B., L.L. and R.C.M. designed the experiments, interpreted the results and wrote the paper, which was edited by all authors.

Competing interests

R.C.M. and K.D. are on the scientific advisory board of Circuit Therapeutics, Inc., a biotech dedicated to development of novel therapeutics for brain disorders. All other authors declare no competing financial interests.

Corresponding authors

Correspondence to Liqun Luo or Robert C. Malenka.

Reviewer Information Nature thanks P. Kenny, M. Wolf and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI

https://doi.org/10.1038/nature23888

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