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

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

Article and author information

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.

Reviewing Editor

  1. Jun Ding, Stanford University, United States

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.

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.

Metrics

  • 3,442
    views
  • 777
    downloads
  • 20
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.75253

Further reading

    1. Neuroscience
    Ya-Hui Lin, Li-Wen Wang ... Li-An Chu
    Research Article

    Tissue-clearing and labeling techniques have revolutionized brain-wide imaging and analysis, yet their application to clinical formalin-fixed paraffin-embedded (FFPE) blocks remains challenging. We introduce HIF-Clear, a novel method for efficiently clearing and labeling centimeter-thick FFPE specimens using elevated temperature and concentrated detergents. HIF-Clear with multi-round immunolabeling reveals neuron circuitry regulating multiple neurotransmitter systems in a whole FFPE mouse brain and is able to be used as the evaluation of disease treatment efficiency. HIF-Clear also supports expansion microscopy and can be performed on a non-sectioned 15-year-old FFPE specimen, as well as a 3-month formalin-fixed mouse brain. Thus, HIF-Clear represents a feasible approach for researching archived FFPE specimens for future neuroscientific and 3D neuropathological analyses.

    1. Neuroscience
    Amanda Chu, Nicholas T Gordon ... Michael A McDannald
    Research Article

    Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior theoretically linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is theoretically linked to imminent or occurring predation. A criticism of studies observing fear conditioned cue-elicited locomotion is that responding is non-associative. We gave rats Pavlovian fear discrimination over a baseline of reward seeking. TTL-triggered cameras captured 5 behavior frames/s around cue presentation. Experiment 1 examined the emergence of danger-specific behaviors over fear acquisition. Experiment 2 examined the expression of danger-specific behaviors in fear extinction. In total, we scored 112,000 frames for nine discrete behavior categories. Temporal ethograms show that during acquisition, a fear conditioned cue suppresses reward seeking and elicits freezing, but also elicits locomotion, jumping, and rearing - all of which are maximal when foot shock is imminent. During extinction, a fear conditioned cue most prominently suppresses reward seeking, and elicits locomotion that is timed to shock delivery. The independent expression of these behaviors in both experiments reveal a fear conditioned cue to orchestrate a temporally organized suite of behaviors.