Cited by 1,885Deep Brain Stimulation and Movement DisordersParkinson's Disease Mechanisms and TreatmentsMotor Control and Adaptation

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Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

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Kravitz, Alexxai V., Freeze, Benjamin S., Parker, Philip R. L., Kay, Kenneth, Thwin, Myo T., Deisseroth, Karl, Kreitzer, Anatol C.·2010·Nature

DOI 10.1038/nature09159PMC PMC3552484

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Abstract

Neural circuits of the basal ganglia are critical for motor planning and action selection. Two parallel basal ganglia pathways have been described, and have been proposed to exert opposing influences on motor function. According to this classical model, activation of the 'direct' pathway facilitates movement and activation of the 'indirect' pathway inhibits movement. However, more recent anatomical and functional evidence has called into question the validity of this hypothesis. Because this model has never been empirically tested, the specific function of these circuits in behaving animals remains unknown. Here we report direct activation of basal ganglia circuitry in vivo, using optogenetic control of direct- and indirect-pathway medium spiny projection neurons (MSNs), achieved through Cre-dependent viral expression of channelrhodopsin-2 in the striatum of bacterial artificial chromosome transgenic mice expressing Cre recombinase under control of regulatory elements for the dopamine D1 or D2 receptor. Bilateral excitation of indirect-pathway MSNs elicited a parkinsonian state, distinguished by increased freezing, bradykinesia and decreased locomotor initiations. In contrast, activation of direct-pathway MSNs reduced freezing and increased locomotion. In a mouse model of Parkinson's disease, direct-pathway activation completely rescued deficits in freezing, bradykinesia and locomotor initiation. Taken together, our findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

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Authors: Kravitz, A. V., Freeze, B. S., Parker, P. R. L., Kay, K., Thwin, M. T., Deisseroth, K., & Kreitzer, A. C.
Affiliations: Gladstone Institutes (US)
Stanford University (US)
Corresponding author: Kreitzer, Anatol C.
ORCID: Kravitz, Alexxai V.
Freeze, Benjamin S.
Parker, Philip R. L.
Kay, Kenneth
Thwin, Myo T.
Deisseroth, Karl
Kreitzer, Anatol C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2010-07
Volume: 466
Issue: 7306
Pages: 622-626
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09159
PMC: PMC3552484
OpenAlex: W1971797700
Cited by: 1,885
References: 28
Citations by year: 2026: 76 · 2025: 110 · 2024: 138 · 2023: 110 · 2022: 96 · 2021: 120 · 2020: 118 · 2019: 119 · 2018: 137 · 2017: 133 · 2016: 128 · 2015: 138 · 2014: 133 · 2013: 112 · 2012: 100
FWCI: 62.12
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: W. M. Keck Foundation
McKnight Foundation
National Institutes of Health
University of California, San Francisco
National Institute of Neurological Disorders and Stroke (R01NS064984)
Topics: Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
Keywords: basal ganglia, Parkinson's disease, direct pathway, indirect pathway, medium spiny neurons, striatum, optogenetics, channelrhodopsin-2, dopamine D1 receptor, dopamine D2 receptor, locomotion, bradykinesia, freezing behavior, motor control, functional connectivity, mouse model of Parkinson's disease, viral gene expression, Cre recombinase
MeSH terms: Channelrhodopsins, Animals, Basal Ganglia, Disease Models, Animal, Gait, Mice, Transgenic, Models, Neurological, Motor Activity, Neural Pathways, Neurons, Parkinson Disease, Psychomotor Performance, Receptors, Dopamine, Oxidopamine, Neostriatum, Hypokinesia, Integrases, Chromosomes, Artificial, Bacterial, Mice

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Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry

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