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Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice

Nature Neuroscience volume 20, pages 815823 (2017) | Download Citation

Abstract

The identification of distinct cell types in the basal ganglia has been critical to our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has remained an untapped resource for therapeutic interventions. Here we demonstrate that optogenetic interventions that dissociate the activity of two neuronal populations in the GPe, elevating the activity of parvalbumin (PV)-expressing GPe neurons over that of Lim homeobox 6 (Lhx6)-expressing GPe neurons, restores movement in dopamine-depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine.

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Acknowledgements

The authors thank V. Corbit (University of Pittsburgh) and T. Whalen (Carnegie Mellon University) for Matlab analysis scripts and B. Rogowski (Carnegie Mellon University) for surgical support and behavioral video editing. We also thank N. Kessaris (University of College London) and H. Zeng (Allen Institute) for their gifts of the Lhx6-iCre and Pvalb-2A-Cre mice, respectively. This work was supported by NIH grants F31 NS090745-01 (K.M.), F31 NS093944-01 (A.W.) and R00 NS076524, NSF grant DMS 1516288, and grants from the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Grant), the Parkinson's Disease Foundation, and the NIH Intramural Research Program.

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Affiliations

  1. Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Kevin J Mastro
  2. Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.

    • Kevin T Zitelli
    • , Amanda M Willard
    •  & Aryn H Gittis
  3. Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Kimberly H Leblanc
    •  & Alexxai V Kravitz

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Contributions

K.J.M., K.T.Z., and K.H.L. performed behavioral experiments, including the histological verification, and with A.H.G. analyzed the data. K.J.M. and A.M.W. were responsible for the collection and analysis of the in vivo experiments. All authors discussed results and interpretations. K.J.M. and A.H.G. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Aryn H Gittis.

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DOI

https://doi.org/10.1038/nn.4559

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