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

Jonathan S Schor; Isabelle Gonzalez Montalvo; Perry WE Spratt; Rea J Brakaj; Jasmine A Stansil; Emily L Twedell; Kevin J Bender; Alexandra B Nelson

doi:10.7554/eLife.75253

eLife (Jul 2022)

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

Jonathan S Schor,
Isabelle Gonzalez Montalvo,
Perry WE Spratt,
Rea J Brakaj,
Jasmine A Stansil,
Emily L Twedell,
Kevin J Bender,
Alexandra B Nelson

Affiliations

Jonathan S Schor: ORCiD; Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States
Isabelle Gonzalez Montalvo: Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States
Perry WE Spratt: Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States
Rea J Brakaj: Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States
Jasmine A Stansil: Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States
Emily L Twedell: Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States
Kevin J Bender: ORCiD; Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States
Alexandra B Nelson: ORCiD; Neuroscience Program, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, United States; Weill Institute for Neuroscience, University of California,, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States

DOI: https://doi.org/10.7554/eLife.75253
Journal volume & issue: Vol. 11

Abstract

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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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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