The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism

Crompe, Brice de la; Aristieta, Asier; Leblois, Arthur; Elsherbiny, Salma; Boraud, Thomas; Mallet, Nicolas

doi:10.1038/s41467-020-15352-3

Cited by 80 publications

(72 citation statements)

References 75 publications

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“…These results were identical when considering a larger dataset that included all the putative GP neurons ( Figure S6, supplementary table 12). Such differential firing responses toward STN inputs is consistent with our previous findings in rats in which opto-excitation of STN neurons led to quick excitation in prototypic neurons but inhibition in arkypallidal neurons (Crompe et al, 2020). Thus, similar to D2-SPN inputs, activation of STN glutamatergic afferents impact preferentially onto prototypic and not arkypallidal neurons.…”

Section: Subthalamic Nucleus Inputs Preferentially Excite Prototypic supporting

confidence: 91%

“…Altogether, these results support the view that D2-SPN inputs differentially impact onto prototypic and arkypallidal neurons with arkypallidal neurons receiving weaker and less numerous projections from D2-SPNs as compared to prototypic neurons. Because prototypic neurons efficiently controlled BG network dynamics (Crompe et al, 2020) through their widespread local (i.e. intra GP) and distal projections (Bevan et al, 1998;Fujiyama et al, 2016;Kita and Kita, 1994;Mallet et al, 2012;Sato et al, 2000), their preferential inhibition by D2-SPNs will therefore cause a disinhibition in arkypallidal and STN neurons as revealed by their increased firing in vivo.…”

Section: Striatopallidal Inputs Differentially Impact Onto Prototypicmentioning

confidence: 99%

“…Although disinhibition mechanisms from prototypic neurons has been shown to account for the increased firing observed in the STN following GP opto-inhibition (Crompe et al, 2020;Kovaleski et al, 2020), the increased firing of arkypallidal neurons upon D2-SPN opto-excitation could alternatively be driven by the concurrent increase of STN firing. To better dissect the network mechanism and test if a disinhibition or a direct excitation is leading to an increased firing of arkypallidal neurons, we generated a D2-Cre::Vglut2-Cre double transgenic mouse line that provides the opportunity to opto-manipulate D2-SPNs and STN neurons independently in the same animal.…”

Section: Opto-inhibition Of Stn Neurons Increased the Firing Rate Of mentioning

confidence: 99%

“…In particular, one limiting aspect is the key contribution of the GP in these circuits which has been previously overlooked (Gittis et al, 2014). Indeed, the GP is a hub nucleus at the interface of the indirect and hyperdirect pathways integrating a large amount of striatal D2-SPN and STN inputs, while its long-range GABAergic projections target the whole BG to control and orchestrate BG neuronal activity (Bevan et al, 1998;Crompe et al, 2020;Dodson et al, 2015;Fujiyama et al, 2016;Glajch et al, 2016;Kita, 2007;Mallet et al, 2012Mallet et al, , 2016Mastro et al, 2014Mastro et al, , 2017Sato et al, 2000;Smith et al, 1998). Since D2-SPN and STN inputs are of opposite nature at the level of the GP (i.e.…”

Section: Introductionmentioning

confidence: 99%

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A disynaptic circuit in the globus pallidus controls locomotion inhibition

Aristieta

Barresi

Lindi

et al. 2020

Preprint

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Basal ganglia (BG) inhibit movement through two independent pathways, the indirect- and the hyperdirect-pathways. The globus pallidus (GP) has always been viewed as a simple relay within these two pathways, but its importance has changed drastically with the discovery of two functionally-distinct cell types, namely the prototypic and the arkypallidal neurons. Classic BG models suggest that all GP neurons receive GABAergic inputs from striato-pallidal indirect spiny projection neurons and glutamatergic inputs from subthalamic neurons. However, whether this synaptic connectivity scheme applies to both GP cell-types is currently unknown. Here, we optogenetically dissect the input organization of prototypic and arkypallidal neurons and further define the circuit mechanism underlying action inhibition in BG. Our results highlight that an increased activity of arkypallidal neurons is required to inhibit locomotion. Finally, this work supports the view that arkypallidal neurons are part of a novel disynaptic feedback loop that broadcast inhibitory control on movement execution.

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Section: Subthalamic Nucleus Inputs Preferentially Excite Prototypic supporting

confidence: 91%

Section: Striatopallidal Inputs Differentially Impact Onto Prototypicmentioning

confidence: 99%

Section: Opto-inhibition Of Stn Neurons Increased the Firing Rate Of mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A disynaptic circuit in the globus pallidus controls locomotion inhibition

Aristieta

Barresi

Lindi

et al. 2020

Preprint

Self Cite

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“…The phase of the ECoG beta oscillation was tracked and used to control the timing of electrical stimulation (50-70 µA) delivered to the globus pallidus (GP). We chose the GP as the stimulation target because of its key role in the generation of pathological beta oscillations in this model (Mallet et al, 2008, Crompe et al, 2020. By measuring the impact of GP stimulation on the spectral properties of the cortical input signal, we were able to investigate the effects of phase-dependent perturbations of a synchronised network.…”

Section: Resultsmentioning

confidence: 99%

Phase-dependent closed-loop modulation of neural oscillations in vivo

Rothwell

Sharott

2020

Preprint

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Normal brain function is associated with an assortment of oscillations of various frequencies, each reflecting the timing of separate computational processes and levels of synchronization within and between brain areas. Stimulation accurately delivered on a specified phase of a given oscillation provides the opportunity to target individual aspects of brain function. To achieve this, we have developed a highly responsive system to produce a continuous online phase-estimate. In addition to stable oscillations, the system accurately tracks the early cycles of short, transient oscillations and can operate across the frequency range of most established neuronal oscillations (4 to 250 Hz). Here we demonstrate bidirectional modulation of the pathologically elevated parkinsonian beta-band oscillation (around 35 Hz) in 6-OHDA hemi-lesioned rats. Beta phase, monitored using a single channel electrocorticogram above secondary motor cortex, was used to drive electrical stimulation of the globus pallidus on one of eight phases spanning the oscillation cycle. Stimulation of the early ascending phase suppressed the oscillation whereas stimulation of the early descending phase was amplifying. By implementing a rule that prevented stimulation when the phase estimate was unstable, we achieved a system that could adapt stimulation rate and pattern to respond to the changes produced in the target oscillation. This allowed the electronic system to create and maintain a state of equilibrium with the biological system resulting in continuous stable modulation of the target oscillation over time. These results demonstrate the feasibility of phase locked stimulation as a more refined strategy for remediation of pathological beta oscillations in the treatment of the motor symptoms of Parkinson's disease. Furthermore, they establish the utility of our algorithm and allow for the potential to assess the contribution of rhythmic activity in neuronal computation across a number of brain systems.

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Unraveling the Complexity of Parkinson's Disease: Insights into Pathogenesis and Precision Interventions

Yan,

Coughlin,

Smolin

et al. 2024

Advanced Science

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, leading to motor and non‐motor symptoms. Early detection before symptom onset is crucial but challenging. This study presents a framework integrating circuit modeling, non‐equilibrium dynamics, and optimization to understand PD pathogenesis and enable precision interventions. Neuronal firing patterns, particularly oscillatory activity, play a critical role in PD pathology. The basal ganglia network, specifically the subthalamic nucleus‐external globus pallidus (STN‐GPe) circuitry, exhibits abnormal activity associated with motor dysfunction. The framework leverages the non‐equilibrium landscape and flux theory to identify key connections generating pathological activity, providing insights into disease progression and potential intervention points. The intricate STN‐GPe interplay is highlighted, shedding light on compensatory mechanisms within this circuitry may initially counteract changes but later contribute to pathological alterations as disease progresses. The framework addresses the need for comprehensive evaluation methods to assess intervention outcomes. Cross‐correlations between state variables provide superior early warning signals compared to traditional indicators relying on critical slowing down. By elucidating compensatory mechanisms and circuit dynamics, the framework contributes to improved management, early detection, risk assessment, and potential prevention/delay of PD development. This pioneering research paves the way for precision medicine in neurodegenerative disorders.

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The globus pallidus orchestrates abnormal network dynamics in a model of Parkinsonism

Cited by 80 publications

References 75 publications

A disynaptic circuit in the globus pallidus controls locomotion inhibition

A disynaptic circuit in the globus pallidus controls locomotion inhibition

Phase-dependent closed-loop modulation of neural oscillations in vivo

Unraveling the Complexity of Parkinson's Disease: Insights into Pathogenesis and Precision Interventions

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