Learning from Action: Reconsidering Movement Signaling in Midbrain Dopamine Neuron Activity

Neuron, Год журнала: 2019, Номер 104(1), С. 63 - 77

Опубликована: Окт. 1, 2019

Язык: Английский

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Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

Frontiers in Cellular Neuroscience, Год журнала: 2021, Номер 15

Опубликована: Март 2, 2021

Parkinson’s disease (PD) is a progressive neurodegenerative that impairs movement as well causing multiple other symptoms such autonomic dysfunction, rapid eye (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) loss terminals striatum contribute to characteristic motor features. Although therapies ease PD, there are no treatments slow its progression. Accumulating evidence suggests synaptic impairments axonal degeneration precede neuronal cell body loss. Early changes may be target prevent onset Imaging PD patients with radioligands, post-mortem pathologic studies sporadic patients, animal models demonstrate abnormalities presynaptic postsynaptic dendritic spines. Dopaminergic excitatory synapses substantially reduced whether subtypes show defects remains relatively unexplored. Genetic implicate several genes play role at synapse, providing additional support for dysfunction PD. In this review article we: (1) provide occurring before neuron death; (2) describe main implicated could synapse dysfunction; (3) correlations between expression Snca mRNA mouse homologs GWAS demonstrating selective enrichment dopaminergic, cholinergic neurons. Altogether, these findings highlight need novel therapeutics targeting suggest future should explore roles PD-implicated across types circuits.

Язык: Английский

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Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

Cell Reports, Год журнала: 2021, Номер 34(5), С. 108718 - 108718

Опубликована: Фев. 1, 2021

The G protein alpha subunit o (Gαo) is one of the most abundant proteins in nervous system, and pathogenic mutations its gene (GNAO1) cause movement disorder. However, function Gαo ill defined mechanistically. Here, we show that dictates neuromodulatory responsiveness striatal neurons required for control. Using vivo optical sensors enzymatic assays, determine provides a separate transduction channel modulates coupling both inhibitory stimulatory dopamine receptors to cyclic AMP (cAMP)-generating enzyme adenylyl cyclase. Through combination cell-based assays rodent models, demonstrate GNAO1-associated alter neuron-type-specific fashion via dominant-negative loss-of-function mechanisms. Overall, our findings suggest pathological variants specific circuits regulate signals essential executing motor programs.

Язык: Английский

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Striatal synaptic adaptations in Parkinson's disease

Neurobiology of Disease, Год журнала: 2022, Номер 167, С. 105686 - 105686

Опубликована: Март 8, 2022

The striatum is densely innervated by mesencephalic dopaminergic neurons that modulate acquisition and vigor of goal-directed actions habits. This innervation progressively lost in Parkinson's disease (PD), contributing to the defining movement deficits disease. Although boosting signaling with levodopa early course alleviates these deficits, later this strategy leads emergence debilitating dyskinesia. Here, recent advances our understanding how striatal cells circuits adapt progressive de-innervation therapy are discussed. First, we discuss dopamine (DA) depletion triggers cell type-specific, homeostatic changes spiny projection (SPNs) tend normalize activity but also lead disruption synaptic architecture sculpted experience. Second, roles played cholinergic nitric oxide-releasing interneurons adaptations. Third, examine work freely moving mice suggesting alterations spatiotemporal dynamics ensembles contributes PD deficits. Lastly, recently published evidence from a model contrary classical model, pathway imbalance necessary not sufficient produce frank parkinsonism.

Язык: Английский

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Cellular and Synaptic Dysfunctions in Parkinson’s Disease: Stepping Out of the Striatum

Cells, Год журнала: 2019, Номер 8(9), С. 1005 - 1005

Опубликована: Авг. 29, 2019

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in great variety functions, ranging from motor programming and execution to procedural learning, cognition, emotions. This network is also the region primarily affected by degeneration midbrain dopaminergic neurons localized substantia nigra pars compacta (SNc). causes cellular synaptic dysfunctions BG network, which responsible for appearance symptoms Parkinson’s disease. Dopamine (DA) modulation consequences its loss on striatal microcircuit have been extensively studied, because discrete nature DA innervation other nuclei, action outside striatum has considered negligible. However, there growing body evidence supporting functional extrastriatal both excitability transmission. In this review, relevance normal pathological conditions will be discussed.

Язык: Английский

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Regulation of TrkB cell surface expression—a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor

Cell and Tissue Research, Год журнала: 2020, Номер 382(1), С. 5 - 14

Опубликована: Июнь 15, 2020

Abstract Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of nervous system in vertebrates. TrkB activation show substantial differences to other Trk family that mediate responses nerve growth factor neurotrophin-3. Growing evidence suggests cell surface expression highly regulated determines sensitivity neurons brain-derived neurotrophic (BDNF). This translocation depends on co-factors modulators cAMP levels, N-glycosylation, transactivation. process can occur very short time periods resulting rapid modulation target BDNF could represent a mechanism fine-tuning synaptic plasticity communication complex neuronal networks. review focuses those modulatory mechanisms regulate responsiveness control expression.

Язык: Английский

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Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum

eLife, Год журнала: 2021, Номер 10

Опубликована: Май 13, 2021

Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding its influence on the activity target neurons in vivo remains limited. Here, we use two-photon Ca

Язык: Английский

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Restoration and targeting of aberrant neurotransmitters in Parkinson's disease therapeutics

Neurochemistry International, Год журнала: 2022, Номер 156, С. 105327 - 105327

Опубликована: Март 21, 2022

Язык: Английский

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Nigrostriatal dopamine pathway regulates auditory discrimination behavior

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Окт. 8, 2022

Abstract The auditory striatum, the tail portion of dorsal striatum in basal ganglia, is implicated perceptual decision-making, transforming stimuli to action outcomes. Despite its known connections diverse neurological conditions, dopaminergic modulation sensory striatal neuronal activity and behavioral influences remain unknown. We demonstrated that optogenetic inhibition projections from substantia nigra pars compacta specifically impairs mouse choice performance but not movement an frequency discrimination task. In vivo dopamine calcium imaging freely behaving mice revealed this projection modulates tone representations, tone-evoked release inversely correlated with evidence strength tones. Optogenetic D1-receptor expressing neurons pharmacological D1 receptors dampened accuracy. Our study uncovers a phasic mechanism within nigrostriatal system regulates decisions by modulating ongoing perception.

Язык: Английский

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Moving, fast and slow: behavioural insights into bradykinesia in Parkinson’s disease

Brain, Год журнала: 2023, Номер 146(9), С. 3576 - 3586

Опубликована: Март 2, 2023

The debilitating symptoms of Parkinson's disease, including the hallmark slowness movement, termed bradykinesia, were described more than 100 years ago. Despite significant advances in elucidating genetic, molecular and neurobiological changes it remains conceptually unclear exactly why patients with disease move slowly. To address this, we summarize behavioural observations movement discuss these findings a framework optimal control. In this framework, agents optimize time takes to gather harvest rewards by adapting their vigour according reward that is at stake effort needs be expended. Thus, slow movements can favourable when deemed unappealing or very costly. While reduced sensitivity, which makes less inclined work for reward, has been reported appears related mainly motivational deficits (apathy) rather bradykinesia. Increased sensitivity proposed underlie disease. However, careful bradykinesia are inconsistent abnormal computations costs due accuracy constraints energetic expenditure. These inconsistencies resolved considering general disability switch between stable dynamic states contribute an composite cost This account paradoxical such as abnormally relaxation isometric contractions difficulties halting both increase energy A sound understanding mediating motor impairment will vital linking them underlying neural dynamics distributed brain networks grounding future experimental studies well-defined frameworks.

Язык: Английский

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