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Journal of Chemical Neuroanatomy Apr 2019The protein α-synuclein, a major component of Lewy bodies in nigral neurons of aged and Parkinson's disease (PD) patients, normally co-localizes with synaptophysin and...
The protein α-synuclein, a major component of Lewy bodies in nigral neurons of aged and Parkinson's disease (PD) patients, normally co-localizes with synaptophysin and regulates the pool of synaptic vesicles. Our earlier study on substantia nigra pars compacta (SNpc) in an Asian-Indian population, demonstrated an age-associated linear but non-logarithmic increase in soluble α-synuclein without any loss of nigral neurons. Another distinctive finding was the presence of activated microglia in the ventrolateral region of the aged nigra, suggesting sub-threshold neurodegeneration. Since microglia prune dendrites, we evaluated the alterations in dendritic arborisation in the SNpc from autopsied midbrains of Asian-Indians through aging, using Golgi-Kopsch protocol. Further, we evaluated the expression of synaptic proteins, synaptophysin and synaptotagmin-11 as parallel markers of synaptic transmission anomalies. The dendritic arborization pattern was typical of large multipolar neurons. A subtle but non-significant decline in parameters like dendritic length and number of intersections was noted. Thus, the alterations were milder than those reported in PD. In the neurons of the young (till 10 years), faint cytoplasmic immunoreactivity of synaptic proteins was noted. In the adults and elderly, it was membrane-bound or appeared as punctae within neuropil. Both proteins showed a slight age-related decline, suggesting a mild decrease in the synaptic vesicular traffic, affecting the dopamine transmission with age that may manifest as minor motor disabilities in the elderly. Mapping the differences in synaptic profiles in differentially susceptible ethnic populations, could reveal interesting insights. Thus, nigra of aged individuals and PD patients share pathogenic features that differ in magnitude.
Topics: Adult; Aged; Aging; Female; Humans; Infant; Male; Middle Aged; Neuronal Plasticity; Neurons; Parkinson Disease; Pars Compacta; Synaptophysin; Synaptotagmins
PubMed: 30738909
DOI: 10.1016/j.jchemneu.2019.02.001 -
Movement Disorders : Official Journal... Mar 2017In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with...
BACKGROUND
In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T / T2*-weighted contrasts to define the regions of interest in the SN. Given that T / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately.
OBJECTIVES
To examine regions of the SNpc, defined by neuromelanin-sensitive MRI, exhibiting iron deposition in PD.
METHODS
T -weighted and susceptibility weighted imaging data were obtained in a cohort of 82 subjects (54 controls and 28 PD patients). The PD patients were clinically diagnosed with an average UPDRS-III score of 37.9 ± 12.5 in the off medication state. Susceptibility weighted imaging data were analyzed using SNpc regions of interest defined by neuromelanin-sensitive MRI.
RESULTS
Compared to control subjects, significantly more hypointense signal was observed in the SNpc defined by neuromelanin-sensitive MRI in the PD patients. In the PD group, the lateral ventral region of SNpc exhibited the greatest increase of hypointensity. This increase in the lateral ventral region of SNpc robustly differentiated PD patients from controls.
CONCLUSION
T2*-weighted hypointense signal in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. It is most likely a measure sensitive to PD-related iron deposition and may serve as a robust biomarker of PD. © 2016 International Parkinson and Movement Disorder Society.
Topics: Aged; Female; Humans; Iron; Magnetic Resonance Imaging; Male; Melanins; Middle Aged; Parkinson Disease; Pars Compacta
PubMed: 28004859
DOI: 10.1002/mds.26883 -
Neural Plasticity 2016A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also... (Review)
Review
A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also regulate adult mDA neuron survival and physiology. Mouse models with targeted disruption of some of these genes display several features reminiscent of Parkinson disease (PD), in particular the selective and progressive loss of mDA neurons in the substantia nigra pars compacta (SNpc). The characterization of these animal models has provided valuable insights into various mechanisms of PD pathogenesis. Therefore, the dissection of the mechanisms and survival signalling pathways engaged by these transcription factors to protect mDA neuron from degeneration can suggest novel therapeutic strategies. The work on En1/2-mediated neuroprotection also highlights the potential of protein transduction technology for neuroprotective approaches in PD.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Mesencephalon; Mice; Parkinson Disease; Pars Compacta; Signal Transduction; Transcription Factors
PubMed: 26881122
DOI: 10.1155/2016/6097107 -
Frontiers in Neuroscience 2017In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor... (Review)
Review
In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.
PubMed: 28603482
DOI: 10.3389/fnins.2017.00295 -
ACS Chemical Neuroscience Aug 2022Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.
Topics: Dopaminergic Neurons; Humans; Metabolic Syndrome; Oxidative Stress; Parkinson Disease; Pars Compacta; alpha-Synuclein
PubMed: 35856649
DOI: 10.1021/acschemneuro.2c00165 -
ENeuro 2018GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range...
GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.
Topics: Animals; GABAergic Neurons; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Nucleus Accumbens; Pars Compacta; Substantia Nigra; Tyrosine 3-Monooxygenase; Ventral Tegmental Area
PubMed: 30456293
DOI: 10.1523/ENEURO.0381-18.2018 -
Neuropeptides Jun 2023Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons... (Review)
Review
Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. The surviving nigral dopaminergic neurons display altered spontaneous firing activity in Parkinson's disease. The firing rate of nigral dopaminergic neurons decreases long before complete neuronal death and the appearance of parkinsonian symptoms. A mild stimulation could rescue dopaminergic neurons from death and in turn play neuroprotective effects. Several neuropeptides, including cholecystokinin (CCK), ghrelin, neurotensin, orexin, tachykinins and apelin, within the substantia nigra pars compacta play important roles in the modulation of spontaneous firing activity of dopaminergic neurons and therefore involve motor control and motor disorders. Here, we review neuropeptide-induced modulation of the firing properties of nigral dopaminergic neurons. This review may provide a background to guide further investigations into the involvement of neuropeptides in movement control by modulating firing activity of nigral dopaminergic neurons in Parkinson's disease.
Topics: Humans; Dopaminergic Neurons; Parkinson Disease; Neuroprotection; Substantia Nigra; Neuropeptides
PubMed: 37087783
DOI: 10.1016/j.npep.2023.102337 -
The European Journal of Neuroscience May 2019Neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) play central roles in reward-related behaviours. Nonhuman animal studies suggest...
Neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) play central roles in reward-related behaviours. Nonhuman animal studies suggest that these neurons also process aversive events. However, our understanding of how the human VTA and SNC responds to such events is limited and has been hindered by the technical challenge of using functional magnetic resonance imaging (fMRI) to investigate a small structure where the signal is particularly vulnerable to physiological noise. Here we show, using methods optimized specifically for the midbrain (including high-resolution imaging, a novel registration protocol, and physiological noise modelling), a BOLD (blood-oxygen-level dependent) signal to both financial gain and loss in the VTA and SNC, along with a response to nil outcomes that are better or worse than expected in the VTA. Taken together, these findings suggest that the human VTA and SNC are involved in the processing of both appetitive and aversive financial outcomes in humans.
Topics: Adult; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Pars Compacta; Reward; Ventral Tegmental Area; Young Adult
PubMed: 30471149
DOI: 10.1111/ejn.14288 -
Experimental Neurology Mar 1997We have analyzed the neuropathology of the substantia nigra in four cases of progressive supranuclear palsy compared with age-matched controls and patients with... (Comparative Study)
Comparative Study
We have analyzed the neuropathology of the substantia nigra in four cases of progressive supranuclear palsy compared with age-matched controls and patients with Parkinson's disease. Although there are many reports of severe dopaminergic cell loss in progressive supranuclear palsy, the fate of the GABAergic pars reticulata neurones remains unclear. Serial section analysis and fractional counts of pars compacta neurones (identified by their neuromelanin pigment) and pars reticulata neurones (identified using parvalbumin immunohistochemistry) were performed, and the type and distribution of neuropathology were described. Severe neurodegeneration within the dopaminergic pars compacta was seen in all cases of progressive supranuclear palsy and all cases of Parkinson's disease compared with controls. Lewy body pathology was found only in cases of Parkinson's disease, while neurofibrillary tangles were seen only in cases of progressive supranuclear palsy. Tau-positive astrocytes and neuropil threads were occasionally seen in controls and cases of Parkinson's disease (particularly those of advanced age) but were extremely numerous in all cases of progressive supranuclear palsy. There was a similar decrease in parvalbumin immunoreactivity within the pars reticulata in both progressive supranuclear palsy and Parkinson's disease. However, there was a striking 70% reduction in the number of pars reticulata neurones in progressive supranuclear palsy, with no cell loss observed in Parkinson's disease compared with controls. Our results show that both the dopaminergic pars compacta and the GABAergic pars reticulata are significantly damaged in cases of progressive supranuclear palsy. The distribution of neurodegeneration in patients with Parkinson's disease and progressive supranuclear palsy is discussed with respect to the current theories on pathophysiology in basal ganglia circuitry.
Topics: Aged; Aged, 80 and over; Cell Count; Female; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Degeneration; Nerve Net; Neurofibrillary Tangles; Neurons; Parkinson Disease; Parvalbumins; Reference Values; Substantia Nigra; Supranuclear Palsy, Progressive; tau Proteins
PubMed: 9126169
DOI: 10.1006/exnr.1997.6415 -
Journal of Neurochemistry Feb 2019Despite the importance of somatodendritic dopamine (DA) release in the Substantia Nigra pars compacta (SNc), its mechanism remains poorly understood. Using a novel...
Despite the importance of somatodendritic dopamine (DA) release in the Substantia Nigra pars compacta (SNc), its mechanism remains poorly understood. Using a novel approach combining fast-scan controlled-adsorption voltammetry (FSCAV) and single-unit electrophysiology, we have investigated the mechanism of somatodendritic release by directly correlating basal (non-stimulated) extracellular DA concentration ([DA] ), with pharmacologically-induced changes of firing of nigral dopaminergic neurons in rat brain slices. FSCAV measurements indicated that basal [DA] in the SNc was 40.7 ± 2.0 nM (at 34 ± 0.5°C), which was enhanced by amphetamine, cocaine, and L-DOPA, and reduced by VMAT2 inhibitor, Ro4-1284. Complete inhibition of firing by TTX decreased basal [DA] , but this reduction was smaller than the effect of D receptor agonist, quinpirole. Despite similar effects on neuronal firing, the larger decrease in [DA] evoked by quinpirole was attributed to cell membrane hyperpolarization and greater reduction in cytosolic free Ca ([Ca ] ). Decreasing extracellular Ca also reduced basal [DA] , despite increasing firing frequency. Furthermore, inhibiting L-type Ca channels decreased basal [DA] , although specific Ca 1.3 channel inhibition did not affect firing rate. Inhibition of sarcoplasmic/endoplasmic reticulum Ca -ATPase (SERCA) also decreased [DA] , demonstrating the importance of intracellular Ca stores for somatodendritic release. Finally, in vivo FSCAV measurements showed that basal [DA] in the SNc was 79.8 ± 10.9 nM in urethane-anesthetized rats, which was enhanced by amphetamine. Overall, our findings indicate that although tonic somatodendritic DA release is largely independent of action potentials, basal [DA] is strongly regulated by voltage-dependent Ca influx and release of intracellular Ca . OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Topics: Action Potentials; Animals; Calcium Signaling; Dopamine; Dopaminergic Neurons; Female; Male; Pars Compacta; Rats; Rats, Wistar
PubMed: 30203851
DOI: 10.1111/jnc.14587