Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry
Open accessAbstract
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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The insula's projection to the striatum underscores its pivotal role in motor control and action selection.
“the insula allocates over one-third of its projection to the striatum, particularly the dorsal region, underscoring its pivotal role in motor control and action selection [21][22][23][24].”
From The Insular Cortex: An Interface Between Sensation, Emotion and Cognition (2024) · cites this paper as [21]
The paper's Abstract links basal ganglia circuitry, including striatal neurons, to motor behavior and action selection. It does not identify a projection from the insula to the striatum or establish a pivotal role for the insula; searches for insula and insular cortex found no such passage in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn a simplified framework, direct and indirect basal ganglia pathways oppose each other, with indirect pathway activation causing net inhibition of thalamus and decreased movement, and direct pathway activation causing net disinhibition and increased movement.
“In a simplified framework, these anatomically distinct pathways have been thought to oppose each other, resulting in net inhibition of thalamus and decrease of movement via activation of the indirect pathway, or net disinhibition (i.e. overall excitation) and increase of movement by activation of the direct pathway (Fig.1) 46,47.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [46]
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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
- Venue
- Nature
- Published
- 2010-07
- Volume
- 466
- Issue
- 7306
- Pages
- 622-626
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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 › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › 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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