Experimental investigation into the role of the subthalamic nucleus (STN) in motor control using optogenetics in mice

Guillaumin, Adriane; Serra, Gian Pietro; Georges, François; Wallén-Mackenzie, Åsa

doi:10.1016/j.brainres.2020.147226

Cited by 29 publications

(27 citation statements)

References 77 publications

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“…Conversely, direct excitation of STN decreased movement in rats ( Figures 2D–H ). Similar results have been observed in mice whereby optogenetic inhibition of STN neurons induces hyperlocomotion ( Schweizer et al, 2014 ; Guillaumin et al, 2020 ; Heston et al, 2020 ; Pamukcu et al, 2020 ) and direct optogenetic excitation of the STN reduces specific locomotion tasks ( Guillaumin et al, 2020 ). These results suggest that STN neuronal activity is capable of bidirectional motor regulation within the indirect pathway and suggests that STN-DBS has an inhibitory effect on STN glutamatergic neurons.…”

Section: Discussionsupporting

confidence: 83%

Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson’s Disease

2022

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a range of motor symptoms. Treatments are focused on dopamine replacement therapy or deep brain stimulation (DBS). The subthalamic nucleus (STN) is a common target for DBS treatment of PD. However, the function of the STN in normal conditions and pathology is poorly understood. Here, we show in rats that optogenetic modulation of STN neuronal activity exerts bidirectional control of motor function, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic manipulation STN neuronal activity under dopamine depleted condition using the bilateral rodent 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease. Optogenetic inhibition of the STN in the absence of dopamine had no impact on motor control yet STN excitation led to pronounced abnormal involuntary movement. Administration of levodopa rescued the abnormal involuntary movements induced by STN excitation. Although dopamine and STN dysfunction are well established in PD pathology, here we demonstrate simultaneous STN over activity and loss of dopamine lead to motor deficits. Moreover, we show the dysfunction of the STN is dependent on dopamine. This study provides evidence that the loss of dopamine and the over activity of the STN are key features of PD motor deficits. These results provide insight into the STN pathology in PD and therapeutic mechanism of targeting the STN for the treatment for PD.

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Section: Discussionsupporting

confidence: 83%

Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson’s Disease

2022

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“…More recently, optogenetic studies in mice show that areal activation of STN excitatory cells disrupts self-initiated bouts of licking ( Fife et al, 2017 ) and that the activation and inactivation of STN-projecting prefrontal cortex neurons reduced and increased inappropriate licking ( Li et al, 2020 ). Bilateral optogenetic inhibition and activation of STN has also been shown to increase and decrease locomotion, respectively ( Guillaumin et al, 2021 ), and such effects can be mediated by certain molecularly defined subpopulations of STN neurons ( Parolari et al, 2021 ). Thus, the hyperdirect pathway stands as an important short-latency cortico-brainstem route for fast control of locomotion.…”

Section: Introductionmentioning

confidence: 99%

Dynamic control of visually guided locomotion through corticosubthalamic projections

2022

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“…Other studies have reported motor effects when GPe neurons are optogenetically excited (Aristieta et al, 2021; Cui et al, 2021a; Lilascharoen et al, 2021). The major excitatory input to the GPe comes from the subthalamic nucleus (STN), which is part of the hyperdirect pathway of the basal ganglia that drives rapid behavioral stopping (Dunovan et al, 2015; Guillaumin et al, 2021; Nambu et al, 2002; Polyakova et al, 2020). It is not known whether the GPe is part of the neural circuitry required for the stopping effects of the hyperdirect pathway.…”

Section: Discussionmentioning

confidence: 99%

The Indirect Pathway of the Basal Ganglia Promotes Negative Reinforcement, But Not Motor Suppression

Isett

Nguyen

Schwenk

et al. 2022

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Optogenetic stimulation of Adora2a receptor expressing spiny projection neurons (A2A-SPN) in the striatum drives locomotor suppression and negative reinforcement, results attributed to activation of the indirect pathway. The sole long-range projection target of A2A-SPNs is the external globus pallidus (GPe). Unexpectedly, we found that inhibition of the GPe did not suppress movement, but did drive robust negative reinforcement in a real-time place preference assay. Within the striatum, A2A-SPNs inhibit other SPNs through a short-range inhibitory collateral network, and we found that optogenetic stimuli that drove motor suppression shared a common mechanism of recruiting this inhibitory collateral network. Our results suggest that the indirect pathway plays a more prominent role in negative reinforcement than in motor control and challenges the assumption that activity of A2A-SPNs is synonymous with indirect pathway activity.

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Experimental investigation into the role of the subthalamic nucleus (STN) in motor control using optogenetics in mice

Cited by 29 publications

References 77 publications

Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson’s Disease

Bidirectional Optogenetic Modulation of the Subthalamic Nucleus in a Rodent Model of Parkinson’s Disease

Dynamic control of visually guided locomotion through corticosubthalamic projections

The Indirect Pathway of the Basal Ganglia Promotes Negative Reinforcement, But Not Motor Suppression

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