Learning critically drives parkinsonian motor deficits through imbalanced striatal pathway recruitment

Cheung, T. H. C.; Ding, Yunmin; Zhuang, Xiaoxi; Kang, Un Jung

doi:10.1073/pnas.2213093120

Cited by 19 publications

(21 citation statements)

References 65 publications

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“…Levodopa (L‐Dopa) and subthalamic deep brain stimulation (STN‐DBS) shift the balance towards the direct pathway and thereby counteract the chronic weakening present in the PD OFF state. (b) In line with a reinforcement‐centred framework, a recent rodent study (Cheung et al, 2023) has shown that Parkinsonian motor decline and medication‐induced rescue are task and experience‐dependent. Mice were trained on two tasks (step/pole task) before unilaterally lesioning dopamine neurons with 6‐hydroxydopamine (6‐OHDA), which induced a contralateral motor deficit (fewer steps with the contralateral paw).…”

Section: Understanding Parkinson's Disease As a Disorder Of Neural Re...mentioning

confidence: 96%

“…By suppressing indirect pathway activity, STN-DBS could reinstate the reinforcement homeostasis that is lost in PD and thereby support the intrinsic dopamine-driven strengthening that remains in PD (see Figures 4a and 3a). (Cheung et al, 2023) has shown that Parkinsonian motor decline and medication-induced rescue are task and experience-dependent. Mice were trained on two tasks (step/pole task) before unilaterally lesioning dopamine neurons with 6-hydroxydopamine (6-OHDA), which induced a contralateral motor deficit (fewer steps with the contralateral paw).…”

Section: Neural Reinforcement As a Target For Adaptive Deep Brain Sti...mentioning

confidence: 99%

“…in parkinsonian mice (Cheung et al, 2023). In summary, both human clinical and experimental animal studies provide complementary insights into the potential role of dopaminergic reinforcement effects in Parkinson's disease.…”

Section: From Basic Research Towards Clinical Applications For Parkin...mentioning

confidence: 99%

“…The most convincing evidence for the neural reinforcement ‐centred viewpoint on Parkinson's disease stems from a recent rodent study that addressed the hypothesis whether motor decline is a consequence of repetition (summarized in Figure 3b) (Cheung et al, 2023). The study trained mice on two separable motor tasks (pole/step task) before unilaterally lesioning their dopamine neurons with 6‐hydroxydopamine (6‐OHDA).…”

Section: Understanding Parkinson's Disease As a Disorder Of Neural Re...mentioning

confidence: 99%

“…A series of rodent studies have reported that spontaneous movement is associated with dopamine release (see Box 1) (Barter et al, 2015; Cheung et al, 2023; Coddington & Dudman, 2019; Dodson et al, 2016; Markowitz et al, 2023). In line with the suggested negative relationship between dopamine and beta, movement is accompanied by a consistent reduction of beta activity, mainly attributed to a reduction in so‐called beta bursts (Feingold et al, 2015).…”

Section: Neural Reinforcement As a Target For Adaptive Deep Brain Sti...mentioning

confidence: 99%

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Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation

Cavallo,

Neumann

2024

Eur J of Neuroscience

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Millions of people suffer from dopamine‐related disorders spanning disturbances in movement, cognition and emotion. These changes are often attributed to changes in striatal dopamine function. Thus, understanding how dopamine signalling in the striatum and basal ganglia shapes human behaviour is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large‐scale brain networks, and accordingly, many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico‐striatal loops sparks the question, of whether dopamine signals in the basal ganglia serve an overarching computational principle. Such a holistic understanding of dopamine functioning could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson's disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition. Finally, we speculate on how therapeutic interventions such as deep brain stimulation may be able to reinstate reinforcement signals and thereby improve treatment strategies for PD in the future.

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Section: Understanding Parkinson's Disease As a Disorder Of Neural Re...mentioning

confidence: 96%

Section: Neural Reinforcement As a Target For Adaptive Deep Brain Sti...mentioning

confidence: 99%

Section: From Basic Research Towards Clinical Applications For Parkin...mentioning

confidence: 99%

Section: Understanding Parkinson's Disease As a Disorder Of Neural Re...mentioning

confidence: 99%

Section: Neural Reinforcement As a Target For Adaptive Deep Brain Sti...mentioning

confidence: 99%

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Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation

Cavallo,

Neumann

2024

Eur J of Neuroscience

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Learning to Have a Long‐Duration Response

Coelho,

Mendonça

2024

Movement Disorders

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Dopamine-based therapies form the cornerstone of Parkinson's disease (PD) treatment. During chronic levodopa (LD) therapy, motor symptoms show a sustained improvement for up to 14 days after stopping therapy, 1 well beyond the clearance of LD from the body. This enduring effect, known as the longduration response (LDR), significantly contributes to the sustained-uniform response to LD in early PD. The loss of LDR is associated with emergence of motor fluctuations, making interventions aimed at maintaining LDR an attractive target. Dopamine plays a crucial role in movement, learning, and reward. 2 While exploring the mechanisms of LDR, Cheung and colleagues 3 discovered that dopamine-dependent motorlearning, even without explicit reward, underlies the LDR.In their study, mice underwent training on two distinct motor tasks without explicit reward. After unilateral dopamine-depletion with 6-hydroxydopamine, mice were re-exposed to one task. Motor deficits gradually emerged over four re-exposure sessions. However, when tested on the other task in session 5, no impairment was observed. This suggests that repetitive motor performance, in the context of dopamine-depletion, leads to task-specific motor impairment-an "unlearning effect" termed "parkinsonian decline" by the authors. Another group was trained twice a day both in the on and off states. Besides the immediate response to LD, cumulative positive effects gradually appeared in the off state over 5 days, persisting after a 3-day LD washout. This mirrors the LDR observed in patients after prolonged LD exposure. Paired with the observation of task-specific parkinsonian decline, it suggests that LDR is a form of dopamine-dependent motor-learning.Parkinsonian decline coincided with under-recruitment of direct pathway spiny projection neurons (dSPNs) and over-recruitment of indirect pathway SPNs (iSPNs). Pharmacological activation of (hypoactive) dSPNs led to an LDR-like similar to the one seen with LD. Simultaneously, D2 agonists, reducing activity of the (hyperactive) iSPNs, partially restored parkinsonian decline. The magnitude of acute therapeutic improvement predicted the magnitude of LDR-like response, irrespective of treatment strategy, suggesting a motor-learning effect. However, D1 agonists led to an over-recruitment of both dSPNs and iSPNs while D2 agonists led to reduction in both pathways' activation. The authors demonstrated that restoring the balance in dSPN:iSPN recruitment, irrespectively of absolute activity, was the best predictor of LDR maintenance.In vivo effects of D1/D2 acting-drugs are more complex than expected by rate-models. 4 Balancing "relative activity" of striatal pathways, more than modulating "absolute activity" can become a therapeutic strategy. Multiple combinations of D1 agonists and D2 agonists/antagonist can be tested to extend LDR. The authors showed that repeated motor-training in off state may lead to motor decline. This suggests that physical activity schedules should be optimized during good on states to maximized benefits in p...

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Distributed dopaminergic signaling in the basal ganglia and its relationship to motor disability in Parkinson's disease

Zhai,

Cui,

Simmons

et al. 2023

Current Opinion in Neurobiology

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Learning critically drives parkinsonian motor deficits through imbalanced striatal pathway recruitment

Cited by 19 publications

References 65 publications

Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation

Dopaminergic reinforcement in the motor system: Implications for Parkinson's disease and deep brain stimulation

Learning to Have a Long‐Duration Response

Distributed dopaminergic signaling in the basal ganglia and its relationship to motor disability in Parkinson's disease

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