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Cerebellar Purkinje cell microcircuits are essential for tremor

Amanda M Brown, Joshua J White, Meike E van der Heijden, Tao Lin, Roy V Sillitoe
doi: https://doi.org/10.1101/770321
Amanda M Brown
1Department of Pathology and Immunology, Baylor College of Medicine
2Department of Neuroscience, Baylor College of Medicine
4Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA
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Joshua J White
1Department of Pathology and Immunology, Baylor College of Medicine
2Department of Neuroscience, Baylor College of Medicine
4Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA
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Meike E van der Heijden
1Department of Pathology and Immunology, Baylor College of Medicine
4Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA
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Tao Lin
1Department of Pathology and Immunology, Baylor College of Medicine
4Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA
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Roy V Sillitoe
1Department of Pathology and Immunology, Baylor College of Medicine
2Department of Neuroscience, Baylor College of Medicine
3Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine
4Jan and Dan Duncan Neurological Research Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA
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  • For correspondence: sillitoe@bcm.edu
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Abstract

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell activity blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the output of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

Footnotes

  • One Sentence Summary: Genetic, pharmacologic, and optogenetic manipulations demonstrate that Purkinje cells can trigger and propagate the signals for tremor.

  • Competing interests: The authors declare no competing interests.

  • Data and materials availability: All data is available in the main text or the supplementary materials.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted September 15, 2019.
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Cerebellar Purkinje cell microcircuits are essential for tremor
Amanda M Brown, Joshua J White, Meike E van der Heijden, Tao Lin, Roy V Sillitoe
bioRxiv 770321; doi: https://doi.org/10.1101/770321
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Cerebellar Purkinje cell microcircuits are essential for tremor
Amanda M Brown, Joshua J White, Meike E van der Heijden, Tao Lin, Roy V Sillitoe
bioRxiv 770321; doi: https://doi.org/10.1101/770321

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