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Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation

Symptoms of neurological diseases emerge through the dysfunction of neural circuits whose diffuse and intertwined architectures pose serious challenges for delivering therapies. Deep brain stimulation (DBS) improves Parkinson’s disease symptoms acutely but does not differentiate between neuronal circuits, and its effects decay rapidly if stimulation is discontinued. Recent findings suggest that optogenetic manipulation of distinct neuronal subpopulations in the external globus pallidus (GPe) provides long-lasting therapeutic effects in dopamine-depleted (DD) mice. We used synaptic differences to excite parvalbumin-expressing GPe neurons and inhibit lim-homeobox-6–expressing GPe neurons simultaneously using brief bursts of electrical stimulation. In DD mice, circuit-inspired DBS provided long-lasting therapeutic benefits that far exceeded those induced by conventional DBS, extending several hours after stimulation. These results establish the feasibility of transforming knowledge of circuit architecture into translatable therapeutic approaches.

Funding

CIRCUIT MECHANISMS UNDERLYING LONG-LASTING RECOVERY OF MOVEMENT IN DOPAMINE DPELETED MICE INDUCED BY OPTOGENETIC INTERVENTION IN THE GPe

National Institute of Neurological Disorders and Stroke

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DELINEATING CELL-SPECIFIC OUTPUT PATHWAYS OF THE GPe THAT SUPPORT LONG-LASTING BEHAVIORAL RECOVERY IN DOPAMINE DEPLETED MICE

National Institute of Neurological Disorders and Stroke

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DBS Protocols for Long-Lasting Therapeutic Benefit in Mouse and Primate Models of Parkinson's Disease

National Institute of Neurological Disorders and Stroke

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Medical Scientist Training Program

National Institute of General Medical Sciences

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Michael J. Fox Foundation for Parkinson's Research

Richard King Mellon Foundation

Carnegie Mellon University Computational Biology Department Lane Fellowship

Lane Fellowship in Computational Biology IMK

History

Publisher Statement

This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on Vol. 374, Issue 6564, 8 October 2021, DOI: 10.1126/science.abi7852 Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Date

18/08/2021

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