scholarly journals State transitions in the substantia nigra reticulata predict the onset of motor deficits in models of progressive dopamine depletion in mice

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Amanda M Willard ◽  
Brian R Isett ◽  
Timothy C Whalen ◽  
Kevin J Mastro ◽  
Chris S Ki ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
State Transitions ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Dopamine Depletion ◽  
Discrete State ◽  
Substantia Nigra Reticulata ◽  
Diseased State

Parkinson’s disease (PD) is a progressive neurodegenerative disorder whose cardinal motor symptoms are attributed to dysfunction of basal ganglia circuits under conditions of low dopamine. Despite well-established physiological criteria to define basal ganglia dysfunction, correlations between individual parameters and motor symptoms are often weak, challenging their predictive validity and causal contributions to behavior. One limitation is that basal ganglia pathophysiology is studied only at end-stages of depletion, leaving an impoverished understanding of when deficits emerge and how they evolve over the course of depletion. In this study, we use toxin- and neurodegeneration-induced mouse models of dopamine depletion to establish the physiological trajectory by which the substantia nigra reticulata (SNr) transitions from the healthy to the diseased state. We find that physiological progression in the SNr proceeds in discrete state transitions that are highly stereotyped across models and correlate well with the prodromal and symptomatic stages of behavior.

Lack of Spike-Count and Spike-Time Correlations in the Substantia Nigra Reticulata Despite Overlap of Neural Responses

2007 ◽  
Vol 98 (4) ◽  
pp. 2232-2243 ◽  
Author(s):  
Alon Nevet ◽  
Genela Morris ◽  
Guy Saban ◽  
David Arkadir ◽  
Hagai Bergman
Keyword(s):  
Basal Ganglia ◽  
Substantia Nigra ◽  
Information Transfer ◽  
Spike Timing ◽  
Spike Count ◽  
Unique Event ◽  
Correlated Activity ◽  
Different Types ◽  
Substantia Nigra Reticulata ◽  
Response Task

Previous studies of single neurons in the substantia nigra reticulata (SNr) have shown that many of them respond to similar events. These results, as well as anatomical studies, suggest that SNr neurons share inputs and thus may have correlated activity. Different types of correlation can exist between pairs of neurons. These are traditionally classified as either spike-count (“signal” and “noise”) or spike-timing (spike-to-spike and joint peristimulus time histograms) correlations. These measures of neuronal correlation are partially independent and have different implications. Our purpose was to probe the computational characteristics of the basal ganglia output nuclei through an analysis of these different types of correlation in the SNr. We carried out simultaneous multiple-electrode single-unit recordings in the SNr of two monkeys performing a probabilistic delayed visuomotor response task. A total of 113 neurons (yielding 355 simultaneously recorded pairs) were studied. Most SNr neurons responded to one or more task-related events, with instruction cue (69%) and reward (63%) predominating. Response-match analysis, comparing peristimulus time histograms, revealed a significant overlap between response vectors. However, no measure of average correlation differed significantly from zero. The lack of significant SNr spike-count population correlations appears to be an exceptional phenomenon in the brain, perhaps indicating unique event-related processing by basal ganglia output neurons to achieve better information transfer. The lack of spike-timing correlations suggests that the basal high-frequency discharge of SNr neurons is not driven by the common inputs and is probably intrinsic.

scholarly journals A Comprehensive Phenotype of Non-motor Impairments and Distribution of Alpha-Synuclein Deposition in Parkinsonism-Induced Mice by a Combination Injection of MPTP and Probenecid

2021 ◽  
Vol 12 ◽  
Author(s):  
Na-Ra Han ◽  
Yu-Kang Kim ◽  
Sora Ahn ◽  
Tae-Yeon Hwang ◽  
Hyejung Lee ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Thermal Hyperalgesia ◽  
Alpha Synuclein ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Motor Impairments ◽  
Expression Levels ◽  
Olfactory Deficit ◽  
Motor Abnormalities ◽  
Non Motor Symptoms

Parkinson’s disease (PD) is characterized by non-motor symptoms as well as motor deficits. The non-motor symptoms rarely appear individually and occur simultaneously with motor deficits or independently. However, a comprehensive research on the non-motor symptoms using an experimental model of PD remains poorly understood. The aim of the current study is to establish a chronic mouse model of PD mimicking the comprehensive non-motor symptoms of human PD by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid (MPTP/p). The non-motor and motor symptoms were evaluated by performing buried food, short-term olfactory memory, hot plate, open field, tail suspension, Y maze, novel object recognition, bead expulsion, one-h stool collection, rotarod, rearing, catalepsy, and akinesia tests after 10 injections of MPTP/p into mice. The expression levels of α-synuclein, glial fibrillary acidic protein (GFAP), tyrosine hydroxylase (TH) or DJ-1 were analyzed by Western blotting or immunostaining. MPTP/p-treated mice achieved to reproduce the key features of non-motor symptoms including olfactory deficit, thermal hyperalgesia, anxiety, depression, cognitive decline, and gastrointestinal dysfunction in addition to motor deficits. The MPTP/p-treated mice also showed the high levels of α-synuclein and low levels of TH and DJ-1 in striatum, substantia nigra, olfactory bulb, hippocampus, amygdala, prefrontal cortex, locus coeruleus, or colon. In addition, the expression levels of phosphorylated-α-synuclein and GFAP were elevated in the striatum and substantia nigra in the MPTP/p-treated mice. Taken together, our study clarifies that the chronic MPTP/p-treated mice have a variety of non-motor dysfunctions as well as motor abnormalities by α-synuclein overexpression and dopaminergic depletion. Therefore, the study of comprehensive phenotypes of non-motor symptoms in one PD model would advance in-depth understandings of neuropathological alternations and contribute to future strategies for PD treatment.

scholarly journals The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Andrew Lutas ◽  
Carolina Lahmann ◽  
Magali Soumillon ◽  
Gary Yellen
Keyword(s):  
Basal Ganglia ◽  
Substantia Nigra ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Substantia Nigra Pars Reticulata ◽  
Motor Deficits ◽  
Tonic Firing ◽  
Leak Channel ◽  
Individual Mouse ◽  
Severe Motor

Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN.

scholarly journals Motor thalamus supports striatum-driven reinforcement

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Arnaud L Lalive ◽  
Anthony D Lien ◽  
Thomas K Roseberry ◽  
Christopher H Donahue ◽  
Anatol C Kreitzer
Keyword(s):  
Synaptic Plasticity ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Projection Neurons ◽  
Direct Pathway ◽  
Substantia Nigra Reticulata ◽  
Motor Thalamus ◽  
Self Stimulation ◽  
Stimulation Of

Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it’s unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia output nucleus substantia nigra reticulata (SNr) or activation of SNr targets in the brainstem or thalamus, was also sufficient to drive rapid reinforcement. Remarkably, silencing motor thalamus—but not other selected targets of SNr—was the only manipulation that reduced dMSN-driven reinforcement. Together, these results point to an unexpected role for basal ganglia output to motor thalamus in striatum-driven reinforcement.

scholarly journals Nigral Iron Elevation Is an Invariable Feature of Parkinson’s Disease and Is a Sufficient Cause of Neurodegeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Scott Ayton ◽  
Peng Lei
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Motor Deficits ◽  
Disease Mechanism ◽  
Disease Modifying Therapy ◽  
Disease Modifying Therapies ◽  
Sufficient Cause ◽  
Disease Modifying

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor deficits accompanying degeneration of substantia nigra pars compactor (SNc) neurons. Although familial forms of the disease exist, the cause of sporadic PD is unknown. Symptomatic treatments are available for PD, but there are no disease modifying therapies. While the neurodegenerative processes in PD may be multifactorial, this paper will review the evidence that prooxidant iron elevation in the SNc is an invariable feature of sporadic and familial PD forms, participates in the disease mechanism, and presents as a tractable target for a disease modifying therapy.

scholarly journals Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1007
Author(s):  
E. Maruthi Prasad ◽  
Shih-Ya Hung
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Respiratory Chain ◽  
Current Treatment ◽  
Muscle Rigidity ◽  
Motor Symptoms ◽  
Dopamine Depletion ◽  
Pathologic Features

Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

scholarly journals Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein

2020 ◽  
Vol 6 (18) ◽  
pp. eaba1193 ◽  
Author(s):  
Eunna Chung ◽  
Youngsil Choi ◽  
Jiae Park ◽  
Wonheum Nah ◽  
Jaehyung Park ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
E3 Ubiquitin Ligase ◽  
Intracellular Delivery ◽  
Motor Deficits ◽  
Motor Symptoms ◽  
Body Formation ◽  
Enhanced Solubility ◽  
A Cell

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, Lewy body formation, and loss of dopaminergic neurons. Parkin, an E3 ubiquitin ligase, is thought to inhibit PD progression by removing damaged mitochondria and suppressing the accumulation of α-synuclein and other protein aggregates. The present study describes a protein-based therapy for PD enabled by the development of a cell-permeable Parkin protein (iCP-Parkin) with enhanced solubility and optimized intracellular delivery. iCP-Parkin recovered damaged mitochondria by promoting mitophagy and mitochondrial biogenesis and suppressed toxic accumulations of α-synuclein in cells and animals. Last, iCP-Parkin prevented and reversed declines in tyrosine hydroxylase and dopamine expression concomitant with improved motor function induced by mitochondrial poisons or enforced α-synuclein expression. These results point to common, therapeutically tractable features in PD pathophysiology, and suggest that motor deficits in PD may be reversed, thus providing opportunities for therapeutic intervention after the onset of motor symptoms.

scholarly journals Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice

2020 ◽  
Vol 124 (2) ◽  
pp. 312-329
Author(s):  
Timothy C. Whalen ◽  
Amanda M. Willard ◽  
Jonathan E. Rubin ◽  
Aryn H. Gittis
Keyword(s):  
Basal Ganglia ◽  
D2 Receptor ◽  
Receptor Activation ◽  
Motor Dysfunction ◽  
Motor Symptoms ◽  
Strongly Correlated ◽  
Dopamine Depletion ◽  
Neural Noise ◽  
Novel Method ◽  
Delta Oscillations

This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson’s disease (PD) treatment.

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