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Current Biology : CB Mar 2024Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in...
Dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement speed, and loss of these neurons leads to bradykinesia in Parkinson's disease (PD). However, other aspects of movement vigor are also affected in PD; for example, movement sequences are typically shorter. However, the relationship between the activity of DANs and the length of movement sequences is unknown. We imaged activity of SNc DANs in mice trained in a freely moving operant task, which relies on individual forelimb sequences. We uncovered a similar proportion of SNc DANs increasing their activity before either ipsilateral or contralateral sequences. However, the magnitude of this activity was higher for contralateral actions and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-modulated DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal and invigorate aspects of contralateral movements.
Topics: Mice; Animals; Dopaminergic Neurons; Substantia Nigra; Movement; Pars Compacta; Parkinson Disease
PubMed: 38377999
DOI: 10.1016/j.cub.2024.01.067 -
Frontiers in Neuroscience 2016Parkinson's disease (PD) is the second most common neurodegenerative disorder. This chronic, progressive disease is characterized by loss of dopaminergic (DA) neurons in... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder. This chronic, progressive disease is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic inclusions called Lewy bodies (LBs) in surviving neurons. PD is attributed to a combination of environment and genetic factors, but the precise underlying molecular mechanisms remain elusive. Oxidative stress is generally recognized as one of the main causes of PD, and excessive reactive oxygen species (ROS) can lead to DA neuron vulnerability and eventual death. Several studies have demonstrated that small non-coding RNAs termed microRNAs (miRNAs) can regulate oxidative stress in vitro and in vivo models of PD. Relevant miRNAs involved in oxidative stress can prevent ROS-mediated damage to DA neurons, suggesting that specific miRNAs may be putative targets for novel therapeutic targets in PD.
PubMed: 27445669
DOI: 10.3389/fnins.2016.00298 -
Frontiers in Neuroscience 2018Several lines of evidence place alpha-synuclein (aSyn) at the center of Parkinson's disease (PD) etiology, but it is still unclear why overexpression or mutated forms of... (Review)
Review
Several lines of evidence place alpha-synuclein (aSyn) at the center of Parkinson's disease (PD) etiology, but it is still unclear why overexpression or mutated forms of this protein affect some neuronal populations more than others. Susceptible neuronal populations in PD, dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the locus coeruleus (LC), are distinguished by relatively high cytoplasmic concentrations of dopamine and calcium ions. Here we review the evidence for the multi-hit hypothesis of neurodegeneration, including recent papers that demonstrate synergistic interactions between aSyn, calcium ions and dopamine that may lead to imbalanced protein turnover and selective susceptibility of these neurons. We conclude that decreasing the levels of any one of these toxicity mediators can be beneficial for the survival of SNpc and LC neurons, providing multiple opportunities for targeted drug interventions aimed at modifying the course of PD.
PubMed: 29593491
DOI: 10.3389/fnins.2018.00161 -
Neurobiology of Aging Mar 2020Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or...
Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or whether these markers predict aspects of cognition. Here, we use high-resolution diffusion-weighted MRI to investigate microstructural and compositional changes in LC and SNpc in young and older adult cohorts, as well as their relationship with cognition. In LC, the older cohort exhibited a significant reduction in mean and radial diffusivity, but a significant increase in fractional anisotropy compared with the young cohort. We observed a significant correlation between the decrease in LC mean, axial, and radial diffusivities and measures examining cognition (Rey Auditory Verbal Learning Test delayed recall) in the older adult cohort. This observation suggests that LC is involved in retaining cognitive abilities. In addition, we observed that iron deposition in SNpc occurs early in life and continues during normal aging.
Topics: Adult; Aged; Aged, 80 and over; Aging; Cognition; Diffusion Tensor Imaging; Female; Humans; Iron; Locus Coeruleus; Male; Pars Compacta; Young Adult
PubMed: 31870645
DOI: 10.1016/j.neurobiolaging.2019.11.016 -
Investigative Ophthalmology & Visual... May 2022Neurons are the bricks of the neuronal system and experimental access to certain neuron subtypes will be of great help to decipher neuronal circuits. Here, we identified...
PURPOSE
Neurons are the bricks of the neuronal system and experimental access to certain neuron subtypes will be of great help to decipher neuronal circuits. Here, we identified trophoblast glycoprotein (TPBG)-expressing GABAergic amacrine cells (ACs) that were selectively labeled in DAT-tdTomato transgenic mice.
METHODS
Retina and brain sections were prepared for immunostaining with antibodies against various biomarkers. Patch-sequencing was performed to obtain the transcriptomes of tdTomato-positive cells in DAT-tdTomato mice. Whole-cell recordings were conducted to identify responses to light stimulation.
RESULTS
Tyrosine hydroxylase immunoreactive cells were colocalized with tdTomato-positive cells in substantia nigra pars compacta, but not in the retina. Transcriptomes collected from tdTomato-positive cells in retinas via Patch-sequencing exhibited the expression of marker genes of ACs (Pax6 and Slc32a1) and marker genes of GABAergic neurons (Gad1, Gad2, and Slc6a1). Immunostaining with antibodies against relevant proteins (GAD67, GAD65, and GABA) also confirmed transcriptomic results. Furthermore, tdTomato-positive cells in retinas selectively expressed Tpbg, a marker gene for distinct clusters molecularly defined, which was proved with TPBG immunoreactivity in fluorescently labeled cells. Finally, tdTomato-positive cells recorded showed ON-OFF responses to light stimulation.
CONCLUSIONS
Ectopic expression occurs in the retina but not in the substantia nigra pars compacta in the DAT-tdTomato mouse, and fluorescently labeled cells in the retina are TPBG-expressing GABAergic ACs. This type of transgenic mice has been proved as an ideal tool to achieve efficient labeling of a distinct subset of ACs that selectively express Tpbg.
Topics: Amacrine Cells; Animals; Antigens, Surface; Luminescent Proteins; Membrane Glycoproteins; Mice; Mice, Transgenic; Retina; Red Fluorescent Protein
PubMed: 35551574
DOI: 10.1167/iovs.63.5.13 -
Cells Nov 2022Neuromelanin granules (NMGs) are organelle-like structures present in the human . In addition to neuromelanin, NMGs contain proteins, lipids and metals. As...
Neuromelanin granules (NMGs) are organelle-like structures present in the human . In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson's disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SN) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB.
Topics: Humans; Proteome; alpha-Synuclein; Proteomics; Lewy Body Disease
PubMed: 36428966
DOI: 10.3390/cells11223538 -
Pharmacology, Biochemistry, and Behavior Jan 2021Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying... (Review)
Review
Opioid abuse and related overdose deaths continue to rise in the United States, contributing to the national opioid crisis in the USA. The neural mechanisms underlying opioid abuse and addiction are still not fully understood. This review discusses recent progress in basic research dissecting receptor mechanisms and circuitries underlying opioid reward and addiction. We first review the canonical GABA-dopamine neuron hypothesis that was upheld for half a century, followed by major findings challenging this hypothesis. We then focus on recent progress in research evaluating the role of the mesolimbic and nigrostriatal dopamine circuitries in opioid reward and relapse. Based on recent findings that activation of dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is equally rewarding and that GABA neurons in the rostromedial tegmental nucleus (RMTg) and the substantia nigra pars reticula (SNr) are rich in mu opioid receptors and directly synapse onto midbrain DA neurons, we proposed that the RTMg→VTA → ventrostriatal and SNr → SNc → dorsostriatal pathways may act as the two major neural substrates underlying opioid reward and abuse. Lastly, we discuss possible integrations of these two pathways during initial opioid use, development of opioid abuse and maintenance of compulsive opioid seeking.
Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Dopamine; Dopaminergic Neurons; Humans; Mesencephalon; Neural Pathways; Opioid-Related Disorders; Pars Compacta; Pars Reticulata; Receptors, Opioid, mu; Reward; Synapses; Ventral Tegmental Area; gamma-Aminobutyric Acid
PubMed: 33227308
DOI: 10.1016/j.pbb.2020.173072 -
Heliyon Jun 2023Curcumin is a natural compound with extensive pharmacological effects. This research is to verify the optimal dose and administration duration efficacy of curcumin in...
BACKGROUND
Curcumin is a natural compound with extensive pharmacological effects. This research is to verify the optimal dose and administration duration efficacy of curcumin in alleviating the movement symptoms of Parkinson's disease (PD).
METHODS
Wistar rats were divided into six groups including control, model, levodopa treatment and low/middle/high (40/80/160 mg/kg/d) curcumin treatment groups. After stereotactic brain injection of 6-hydroxydopamine (6-OHDA), curcumin was given by intragastric administration for 2 weeks. To evaluate the drug effect, the rats received behavioral tests including apomorphine (APO)-induced rotation test, rotarod test and open field test. Then the rats were sacrificed and the brain slices including substantia nigra pars compacta (SNc) were used for immunofluorescence staining.
RESULTS
After 6-OHDA injection, the model group showed typical movement symptoms including the severe APO-induced rotation to the healthy side, decreased latency in the rotarod with constant or accelerative mode, and decreased total distance and average speed in the open field test. In the results of immunofluorescence staining, the 6-OHDA induced a severe damage of dopaminergic neurons in SNc. The 160 mg/kg/d treatment of curcumin to intervene for 2 weeks alleviated most of the behavioral disorders but the 40/80 mg/kg/d treatment showed limitations. Then, we compared the effect of 1 week intervention to the 2 weeks with 160 mg/kg/d treatment of curcumin to intervene and results indicated that the treatment of 2 weeks could better alleviate the symptoms.
CONCLUSIONS
Curcumin alleviated 6-OHDA-induced movement symptoms in a PD rat model. Additionally, the effect of curcumin against PD indicated dose and duration dependent and the intervention of 160 mg/kg/d for 2 weeks showed optimally therapeutic effect.
PubMed: 37484231
DOI: 10.1016/j.heliyon.2023.e16921 -
Pharmacology 2014The major hallmark of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the characteristic motor... (Review)
Review
The major hallmark of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the characteristic motor symptoms of resting tremors, bradykinesia and rigidity. Research in the field of PD therapy has been partly successful in terms of developing symptomatic treatments, but it also experienced several failures with regard to developing disease-modifying therapies. According to the definition of the Committee to Identify Neuroprotective Agents for Parkinson's, neuroprotection would be any intervention that favorably influences the disease process or underlying pathogenesis to produce enduring benefits for patients. A development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages. Novel solutions might be offered by an evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multitarget approaches and network pharmacology. Several promising randomized controlled trials are in progress, and the increased collaboration between pharmaceutical companies and basic and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of PD. The aim of the present review is to give an overview of the neuroprotective agents and their targets currently investigated for the treatment of PD in phase I-III clinical trials.
Topics: Animals; Antiparkinson Agents; Drug Design; Humans; Neuroprotective Agents; Parkinson Disease
PubMed: 25096413
DOI: 10.1159/000362419 -
Frontiers in Neuroscience 2021Parkinson's disease (PD) is a major neurodegenerative disease characterized by massive degeneration of the dopaminergic neurons in the substantia nigra pars compacta,... (Review)
Review
Parkinson's disease (PD) is a major neurodegenerative disease characterized by massive degeneration of the dopaminergic neurons in the substantia nigra pars compacta, α-synuclein-containing Lewy bodies, and neuroinflammation. Magnetic resonance (MR) imaging plays a crucial role in the diagnosis and monitoring of disease progression and treatment. A variety of MR methods are available to characterize neurodegeneration and other disease features such as iron accumulation and metabolic changes in animal models of PD. This review aims at giving an overview of how those physiopathological features of PD have been investigated using various MR methods in rodent models. Toxin-based and genetic-based models of PD are first described. MR methods for neurodegeneration evaluation, iron load, and metabolism alterations are then detailed, and the main findings are provided in those models. Ultimately, future directions are suggested for neuroinflammation and neuromelanin evaluations in new animal models.
PubMed: 33897339
DOI: 10.3389/fnins.2021.583678