1. Neuroscience

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in Parkinsonian mice

  1. Jonathan S Schor
  2. Isabelle Gonzalez Montalvo
  3. Perry WE Spratt
  4. Rea J Brakaj
  5. Jasmine A Stansil
  6. Emily L Twedell
  7. Kevin J Bender
  8. Alexandra B Nelson  Is a corresponding author
  1. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.75253
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  1. Jonathan S Schor
  2. Isabelle Gonzalez Montalvo
  3. Perry WE Spratt
  4. Rea J Brakaj
  5. Jasmine A Stansil
  6. Emily L Twedell
  7. Kevin J Bender
  8. Alexandra B Nelson
(2022)
Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in Parkinsonian mice
eLife 11:e75253.
https://doi.org/10.7554/eLife.75253
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Abstract

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's Disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

Data availability

Source data can be found on Dryad, doi:10.7272/Q60P0X95.

The following data sets were generated

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Author details

  1. Jonathan S Schor

    Neuroscience Program, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2806-8782

  2. Isabelle Gonzalez Montalvo

    Neuroscience Program, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Perry WE Spratt

    Neuroscience Program, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Rea J Brakaj

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jasmine A Stansil

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Emily L Twedell

    Neuroscience Program, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Kevin J Bender

    Department of Neurology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7084-1532

  8. Alexandra B Nelson

    Neuroscience Program, University of California, San Francisco, San Francisco, United States
    For correspondence
    Alexandra.Nelson@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9305-5662

Funding

Aligning Science Across Parkinson's (ASAP-020529)

  • Alexandra B Nelson

National Institutes of Health (F31 NS110329)

  • Jonathan S Schor

National Institutes of Health (K08 NS081001)

  • Alexandra B Nelson

National Institutes of Health (R01NS101354)

  • Alexandra B Nelson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were approved by the UC San Francisco institutional animal care and use committee (IACUC), protocol # AN189295. Efforts were made throughout to minimize the suffering of animals by use of appropriate anesthetics and analgesics, as well as enrichment and supportive care.

Reviewing Editor

  1. Jun Ding, Stanford University, United States

Version history

  1. Received: November 4, 2021
  2. Preprint posted: November 13, 2021 (view preprint)
  3. Accepted: July 1, 2022
  4. Accepted Manuscript published: July 4, 2022 (version 1)
  5. Version of Record published: August 1, 2022 (version 2)

Copyright

© 2022, Schor et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jonathan S Schor
  2. Isabelle Gonzalez Montalvo
  3. Perry WE Spratt
  4. Rea J Brakaj
  5. Jasmine A Stansil
  6. Emily L Twedell
  7. Kevin J Bender
  8. Alexandra B Nelson
(2022)
Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in Parkinsonian mice
eLife 11:e75253.
https://doi.org/10.7554/eLife.75253

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