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Movement Disorders : Official Journal... Aug 2019Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the... (Review)
Review
Studies of the pathophysiology of parkinsonism (specifically akinesia and bradykinesia) have a long history and primarily model the consequences of dopamine loss in the basal ganglia on the function of the basal ganglia/thalamocortical circuit(s). Changes of firing rates of individual nodes within these circuits were originally considered central to parkinsonism. However, this view has now given way to the belief that changes in firing patterns within the basal ganglia and related nuclei are more important, including the emergence of burst discharges, greater synchrony of firing between neighboring neurons, oscillatory activity patterns, and the excessive coupling of oscillatory activities at different frequencies. Primarily focusing on studies obtained in nonhuman primates and human patients with Parkinson's disease, this review summarizes the current state of this field and highlights several emerging areas of research, including studies of the impact of the heterogeneity of external pallidal neurons on parkinsonism, the importance of extrastriatal dopamine loss, parkinsonism-associated synaptic and morphologic plasticity, and the potential role(s) of the cerebellum and brainstem in the motor dysfunction of Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.
Topics: Animals; Basal Ganglia; Brain Stem; Brain Waves; Cerebellum; Cerebral Cortex; Dopamine; Electroencephalography; Globus Pallidus; Haplorhini; Humans; Neostriatum; Neural Pathways; Neuronal Plasticity; Parkinson Disease; Parkinsonian Disorders; Pars Compacta; Thalamus
PubMed: 31216379
DOI: 10.1002/mds.27741 -
Molecular Brain May 2020Previous studies of the alpha-synuclein null mutant mice on the C57Bl6 genetic background have revealed reduced number of dopaminergic neurons in their substantia nigra...
Previous studies of the alpha-synuclein null mutant mice on the C57Bl6 genetic background have revealed reduced number of dopaminergic neurons in their substantia nigra pars compacta (SNpc). However, the presence in genomes of the studied mouse lines of additional genetic modifications that affect expression of genes located in a close proximity to the alpha-synuclein-encoding Snca gene makes these data open to various interpretations. To unambiguously demonstrate that the absence of alpha-synuclein is the primary cause of the observed deficit of dopaminergic neurons, we employed a recently produced constituent alpha-synuclein knockout mouse line B6(Cg)-Snca/J. The only modification introduced to the genome of these mice is a substitution of the first coding exon and adjusted short intronic fragments of the Snca gene by a single loxP site. We compared the number of dopaminergic neurons in the SNpc of this line, previously studied B6(Cg)-Snca/J line and wild type littermate mice. A similar decrease was observed in both knockout lines when compared with wild type mice. In a recently published study we revealed no loss of dopaminergic neurons following conditional inactivation of the Snca gene in neurons of adult mice. Taken together, these results strongly suggest that alpha-synuclein is required for efficient survival or maturation of dopaminergic neurons in the developing SNpc but is dispensable for survival of mature SNpc dopaminergic neurons.
Topics: Animals; Cell Survival; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Mice, Knockout; Pars Compacta; Substantia Nigra; alpha-Synuclein
PubMed: 32393371
DOI: 10.1186/s13041-020-00613-5 -
Journal of Neural Transmission.... 2009The substantia nigra, located in the ventral mesencephalon, is one of the five nuclei that constitute the basal ganglia circuit, which controls voluntary movements. It... (Review)
Review
The substantia nigra, located in the ventral mesencephalon, is one of the five nuclei that constitute the basal ganglia circuit, which controls voluntary movements. It is divided into the pars compacta and the pars reticulata, which mainly contain dopaminergic and GABAergic cells respectively. Here we overview the electrophysiological properties of these substantia nigra neurons in the pars compacta and reticulata, together with their synaptic connections, and discuss the functional effects of dopaminergic and GABAergic inputs within the basal ganglia. We also examine the phenomenon that when a deficiency of dopamine (DA) occurs (e.g. in Parkinson's disease), there is an aberrant synaptic plasticity in the basal ganglia. Moreover, we point out that the appearance of an altered pattern of neuronal firing (beta-oscillations) and synchrony among neurons in the subthalamic nucleus, the internal globus pallidus, and the substantia nigra pars reticulata has been related to motor symptoms and possibly, persistent degeneration of DA-containing neurons. Finally, we believe that, based on pathophysiological data, new and significant targets for therapeutic intervention can be identified and tested.
Topics: Animals; Basal Ganglia; Dopamine; Humans; Membrane Potentials; Nerve Net; Neural Pathways; Neurons; Parkinson Disease; Substantia Nigra
PubMed: 20411770
DOI: 10.1007/978-3-211-92660-4_7 -
Neurobiology of Disease Oct 2022Dopaminergic neurons in the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's Disease, with the ventral region degenerating more severely... (Review)
Review
Dopaminergic neurons in the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's Disease, with the ventral region degenerating more severely than the dorsal region. Compared with the dorsal neurons, the ventral neurons in the SNc have distinct dendritic morphology, electrophysiological characteristics, and circuit connections with the basal ganglia. These characteristics shape information processing in the ventral SNc and structure the balance of inhibition and disinhibition in the striatonigral circuitry. In this paper, I review foundational studies and recent work comparing the circuitry of the ventral and dorsal SNc neurons and discuss how loss of the ventral neurons early in Parkinson's Disease could affect the overall balance of inhibition and disinhibition of dopamine signals.
Topics: Basal Ganglia; Dopaminergic Neurons; Humans; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 35820645
DOI: 10.1016/j.nbd.2022.105815 -
Neuroscience Letters Nov 2020Parkinson's Disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) therapy can reduce levodopa equivalent daily dose (LEDD) by...
Parkinson's Disease (PD) patients undergoing subthalamic nucleus deep brain stimulation (STN-DBS) therapy can reduce levodopa equivalent daily dose (LEDD) by approximately 50 %, leading to less symptoms of dyskinesia. The underlying mechanisms contributing to this reduction remain unclear, but studies posit that STN-DBS may increase striatal dopamine levels by exciting remaining dopaminergic cells in the substantia nigra pars compacta (SNc). Yet, no direct evidence has shown how SNc neuronal activity responds during STN-DBS in PD. Here, we use a hemiparkinsonian rat model of PD and employ in vivo electrophysiology to examine the effects of STN-DBS on SNc neuronal spiking activity. We found that 43 % of SNc neurons in naïve rats reduced their spiking frequency to 29.8 ± 18.5 % of baseline (p = 0.010). In hemiparkinsonian rats, a higher number of SNc neurons (88 % of recorded cells) decreased spiking frequency to 61.6 ± 4.4 % of baseline (p = 0.030). We also noted that 43 % of SNc neurons in naïve rats increased spiking frequency from 0.2 ± 0.0 Hz at baseline to 1.8 ± 0.3 Hz during stimulation, but only 1 SNc neuron from 1 hemiparkinsonian rat increased its spiking frequency by 12 % during STN-DBS. Overall, STN-DBS decreased spike frequency in the majority of recorded SNc neurons in a rat model of PD. Less homogenous responsiveness in directionality in SNc neurons during STN-DBS was seen in naive rats. Plausibly, poly-synaptic network signaling from STN-DBS may underlie these changes in SNc spike frequencies.
Topics: Action Potentials; Animals; Disease Models, Animal; Electric Stimulation; Male; Neurons; Parkinson Disease; Parkinsonian Disorders; Pars Compacta; Rats, Sprague-Dawley; Subthalamic Nucleus
PubMed: 33141067
DOI: 10.1016/j.neulet.2020.135443 -
Movement Disorders : Official Journal... Nov 2014A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation... (Review)
Review
A hallmark of Parkinson's disease (PD) is the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Dopaminergic denervation is commonly imaged using radiotracer imaging in target structures such as the striatum. Until recently, imaging made only a modest contribution to detecting neurodegenerative changes in the substantia nigra (SN) directly. Histologically, the SN is subdivided into the ventral pars reticulata and the dorsal pars compacta, which is composed of dopaminergic neurons. In humans, dopaminergic neurons, which are known to accumulate neuromelanin, form clusters of cells (nigrosomes) that penetrate deep into the SN pars reticulata (SNr). The SNr contains higher levels of iron than the SNc in normal subjects. Neuromelanin and T2*-weighted imaging therefore better detect the SNc and the SNr, respectively. The development of ultra-high field 7 Tesla (7T) magnetic resonance imaging (MRI) provided the increase in spatial resolution and in contrast that was needed to detect changes in SN morphology. 7T MRI allows visualization of nigrosome-1 as a hyperintense signal area on T2*-weighted images in the SNc of healthy subjects and its absence in PD patients, probably because of the loss of melanized neurons and the increase of iron deposition. This review is designed to provide a better understanding of the correspondence between the outlines and subdivisions of the SN detected using different MRI contrasts and the histological organization of the SN. The recent findings obtained at 7T will then be presented in relation to histological knowledge.
Topics: Female; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Parkinson Disease; Substantia Nigra
PubMed: 25308960
DOI: 10.1002/mds.26043 -
Neuroscience Letters Dec 1986The precise neuronal localization of D1 receptors in the substantia nigra has been studied autoradiographically in the rat by measuring the alterations of [3H]SCH 23390...
The precise neuronal localization of D1 receptors in the substantia nigra has been studied autoradiographically in the rat by measuring the alterations of [3H]SCH 23390 binding site densities in this brain area after 6-hydroxydopamine (6-OHDA) induced destruction of nigrostriatal dopaminergic neurons and after ibotenate-induced lesion of striatal afferents. 6-OHDA-induced nigral lesion provoked a total loss of [3H]SCH 23390 binding sites in the pars compacta and pars lateralis (but not in the pars reticulata) of the substantia nigra. In contrast, ibotenate-induced striatal lesion caused a large diminution of the [3H]ligand binding site density in the pars reticulata but not in the pars compacta and pars lateralis of the substantia nigra. These results suggest that D1 receptors in the pars compacta or pars lateralis of the substantia nigra are located on the dopaminergic perikarya whereas those D1 receptors present in the pars reticulata of the substantia nigra lie on the terminals of nigral afferents of striatal origin.
Topics: Animals; Autoradiography; Benzazepines; Hydroxydopamines; Ibotenic Acid; Male; Oxidopamine; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Stereotaxic Techniques; Substantia Nigra
PubMed: 2950341
DOI: 10.1016/0304-3940(86)90524-0 -
ACS Chemical Neuroscience Jan 2019Parkinson's disease (PD) is a neurodegenerative disease that is pathologically characterized by degeneration of dopamine neurons in the substantia nigra pars compacta... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disease that is pathologically characterized by degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc). PD leads to clinical motor features that include rigidity, tremor, and bradykinesia. Despite multiple available therapies for PD, the clinical features continue to progress, and patients suffer progressive disability. Many advances have been made in PD therapy which directly target the cause of the disease rather than providing symptomatic relief. A neuroprotective or disease modifying strategy that can slow or cease clinical progression and worsening disability remains as a major unmet medical need for PD management. The present review discusses potential novel therapies for PD that include recent interventions in the form of immunomodulatory techniques and stem cell therapy. Further, an introspective approach to identify numerous other novel targets that can alleviate PD pathogenesis and enable physicians to practice multitargeted therapy and that may provide a ray of hope to PD patients in the future are discussed.
Topics: Animals; Antiparkinson Agents; Dopaminergic Neurons; Drug Delivery Systems; Humans; Nerve Regeneration; Neuroprotection; Oxidative Stress; Parkinson Disease; Pars Compacta
PubMed: 29957921
DOI: 10.1021/acschemneuro.8b00180 -
Neurochemical Research May 2002The nigral GABAergic regulation of striatal dopamine release was investigated using voltammetry in freely moving rats. The local administration of muscimol (1 nM) in the... (Comparative Study)
Comparative Study
The nigral GABAergic regulation of striatal dopamine release was investigated using voltammetry in freely moving rats. The local administration of muscimol (1 nM) in the substantia nigra pars compacta, but not in the substantia nigra pars reticulata, increased the striatal dopamine release. In contrast, the administration of baclofen (10 nM) in the substantia nigra pars reticulata, but not in the substantia nigra pars compacta, produced a decrease of the striatal dopamine release. Opposite effects were respectively observed after administration of GABA(A) and GABA(B) antagonists. These data lead us to suggest a differential presynaptic GABAergic control of the dopaminergic neurotransmission through GABA(A) receptors in the substantia nigra pars compacta, and GABA(B) receptors in the substantia nigra pars reticulata.
Topics: Animals; Baclofen; Bicuculline; Corpus Striatum; Dopamine; Electrochemistry; Male; Muscimol; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, GABA-B; Substantia Nigra
PubMed: 12064352
DOI: 10.1023/a:1015595729411 -
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