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1
Niu, Shiba, Weibo Shi, Yingmin Li, Shanyong Yi, Yang Li, Xia Liu, Bin Cong, and Guanglong He. "Endoplasmic Reticulum Stress Is Associated with the Mesencephalic Dopaminergic Neuron Injury in Stressed Rats." Analytical Cellular Pathology 2021 (September 8, 2021): 1–9. http://dx.doi.org/10.1155/2021/7852710.
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An increasing number of people are in a state of stress due to social and psychological pressures, which may result in mental disorders. Previous studies indicated that mesencephalic dopaminergic neurons are associated with not only reward-related behaviors but also with stress-induced mental disorders. To explore the effect of stress on dopaminergic neuron and potential mechanism, we established stressed rat models of different time durations and observed pathological changes in dopaminergic neurons of the ventral tegmental area (VTA) through HE and thionine staining. Immunohistochemistry coupled with microscopy-based multicolor tissue cytometry (MMTC) was employed to investigate the number changes of dopaminergic neurons. Double immunofluorescence labelling was used to investigate expression changes of endoplasmic reticulum stress (ERS) protein GRP78 and CHOP in dopaminergic neurons. Our results showed that prolonged stress led to pathological alteration in dopaminergic neurons of VTA, such as missing of Nissl bodies and pyknosis in dopaminergic neurons. Immunohistochemistry with MMTC indicated that chronic stress exposure resulted in a significant decrease in dopaminergic neurons. Double immunofluorescence labelling showed that the endoplasmic reticulum stress protein took part in the injury of dopaminergic neurons. Taken together, these results indicated the involvement of ERS in mesencephalic dopaminergic neuron injury induced by stress exposure.
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Jovanovic, Predrag, Yidan Wang, Jean-Philippe Vit, Edward Novinbakht, Nancy Morones, Elliot Hogg, Michele Tagliati, and Celine E. Riera. "Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy." PLOS ONE 17, no. 3 (March 22, 2022): e0263074. http://dx.doi.org/10.1371/journal.pone.0263074.
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Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson’s disease. However, non-motor symptoms of Parkinson’s disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson’s disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human α-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate α-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.
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Dodson, Paul D., Jakob K. Dreyer, Katie A. Jennings, Emilie C. J. Syed, Richard Wade-Martins, Stephanie J. Cragg, J. Paul Bolam, and Peter J. Magill. "Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism." Proceedings of the National Academy of Sciences 113, no. 15 (March 21, 2016): E2180—E2188. http://dx.doi.org/10.1073/pnas.1515941113.
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Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.
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Chinta, Shankar J., and Julie K. Andersen. "Dopaminergic neurons." International Journal of Biochemistry & Cell Biology 37, no. 5 (May 2005): 942–46. http://dx.doi.org/10.1016/j.biocel.2004.09.009.
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Na, Junewoo, Byong Seo Park, Doohyeong Jang, Donggue Kim, Thai Hien Tu, Youngjae Ryu, Chang Man Ha, et al. "Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones." International Journal of Molecular Sciences 23, no. 5 (February 26, 2022): 2609. http://dx.doi.org/10.3390/ijms23052609.
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The hypothalamic arcuate nucleus (Arc) is a central unit that controls the appetite through the integration of metabolic, hormonal, and neuronal afferent inputs. Agouti-related protein (AgRP), proopiomelanocortin (POMC), and dopaminergic neurons in the Arc differentially regulate feeding behaviors in response to hunger, satiety, and appetite, respectively. At the time of writing, the anatomical and electrophysiological characterization of these three neurons has not yet been intensively explored. Here, we interrogated the overall characterization of AgRP, POMC, and dopaminergic neurons using genetic mouse models, immunohistochemistry, and whole-cell patch recordings. We identified the distinct geographical location and intrinsic properties of each neuron in the Arc with the transgenic lines labelled with cell-specific reporter proteins. Moreover, AgRP, POMC, and dopaminergic neurons had different firing activities to ghrelin and leptin treatments. Ghrelin led to the increased firing rate of dopaminergic and AgRP neurons, and the decreased firing rate of POMC. In sharp contrast, leptin resulted in the decreased firing rate of AgRP neurons and the increased firing rate of POMC neurons, while it did not change the firing rate of dopaminergic neurons in Arc. These findings demonstrate the anatomical and physiological uniqueness of three hypothalamic Arc neurons to appetite control.
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Orb, Sabine, Johannes Wieacker, Cesar Labarca, Carlos Fonck, Henry A. Lester, and Johannes Schwarz. "Knockin mice with Leu9′Ser α4-nicotinic receptors: substantia nigra dopaminergic neurons are hypersensitive to agonist and lost postnatally." Physiological Genomics 18, no. 3 (August 11, 2004): 299–307. http://dx.doi.org/10.1152/physiolgenomics.00012.2004.
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This study analyzes the electrophysiological cause and behavioral consequence of dopaminergic cell loss in a knockin mouse strain bearing hypersensitive nicotinic α4-receptor subunits (“L9′S mice”). Adult brains of L9′S mice show moderate loss of substantia nigra dopaminergic neurons and of striatal dopaminergic innervation. Amphetamine-stimulated locomotion is impaired, reflecting a reduction of dopamine stored in presynaptic vesicles. Recordings from dopaminergic neurons in L9′S mice show that 10 μM nicotine depolarizes cells and increases spiking rates in L9′S cells but hyperpolarizes and decreases spiking rates in wild-type (WT) cells. Thus dopaminergic neurons of L9′S mice have an excitatory response to nicotine which is qualitatively different from that of WT neurons. The cause of dopaminergic cell death is therefore probably an increased sensitivity to acetylcholine or choline of α4-containing nicotinic receptors. Hypersensitive excitatory stimulation during activation of α4-containing receptors provides the first evidence for cholinergic excitotoxicity as a cause of dopaminergic neuron death. This novel concept may be relevant to the pathophysiology of Parkinson disease.
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Zhang, Nianping, Xudong Zhang, Zhaoli Yan, Ronghui Li, Song Xue, and Dahong Long. "A Modified Differentiation Protocol In Vitro to Generate Dopaminergic Neurons from Pluripotent Stem Cells." Journal of Biomaterials and Tissue Engineering 13, no. 10 (October 1, 2023): 1017–25. http://dx.doi.org/10.1166/jbt.2023.3341.
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Cell transplantation is considered a promising therapeutic strategy for the treatment of Parkinson's disease. Because of their strong differentiation potential, pluripotent stem cells may become a source of dopaminergic neurons for cell transplantation. Although published protocols have revealed that pluripotent stem cells can be successfully induced into dopaminergic neurons, unwanted cell types still exist in PSC-derived cultures. Therefore, signaling parameters for dopaminergic neuron patterning in differentiation protocols need to be further identified and optimized. In this study, we explored an In Vitro modified differentiation protocol for efficiently inducing dopaminergic neurons from pluripotent stem cells. Briefly, pluripotent stem cells were incubated in N2B27 medium for a 4-day culture, and then bFGF, SHH-C24II, purmorphamine, FGF8a and laminin were added to the medium. After a 6-day culture, the medium was replaced with N2B27 medium containing L-ascorbic acid, glial cell line-derived neurotrophic factor, cyclic adenosine monophosphate, laminin, and brain-derived neurotrophic factor for an additional 10 days. We confirmed that combined treatment with bFGF, SHH-C24II, purmorphamine, FGF8a and laminin significantly promoted the differentiation of pluripotent stem cells into dopaminergic neurons. Additionally, we determined a reasonable time window for the use of these factors. Our study provides new insights into the role of cell factors in dopaminergic neuron differentiation of pluripotent stem cells.
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Mendes-Oliveira, Julieta, Filipa L. Campos, Susana A. Ferreira, Diogo Tomé, Carla P. Fonseca, and Graça Baltazar. "Endogenous GDNF Is Unable to Halt Dopaminergic Injury Triggered by Microglial Activation." Cells 13, no. 1 (December 29, 2023): 74. http://dx.doi.org/10.3390/cells13010074.
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Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson’s disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF’s ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor α-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson’s disease.
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SIMON, HORST H., LAVINIA BHATT, DANIEL GHERBASSI, PAOLA SGADÓ, and LAVINIA ALBERÍ. "Midbrain Dopaminergic Neurons." Annals of the New York Academy of Sciences 991, no. 1 (January 24, 2006): 36–47. http://dx.doi.org/10.1111/j.1749-6632.2003.tb07461.x.
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Awata, Hiroko, Mai Takakura, Yoko Kimura, Ikuko Iwata, Tomoko Masuda, and Yukinori Hirano. "The neural circuit linking mushroom body parallel circuits induces memory consolidation in Drosophila." Proceedings of the National Academy of Sciences 116, no. 32 (July 23, 2019): 16080–85. http://dx.doi.org/10.1073/pnas.1901292116.
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Memory consolidation is augmented by repeated learning following rest intervals, which is known as the spacing effect. Although the spacing effect has been associated with cumulative cellular responses in the neurons engaged in memory, here, we report the neural circuit-based mechanism for generating the spacing effect in the memory-related mushroom body (MB) parallel circuits in Drosophila. To investigate the neurons activated during the training, we monitored expression of phosphorylation of mitogen-activated protein kinase (MAPK), ERK [phosphorylation of extracellular signal-related kinase (pERK)]. In an olfactory spaced training paradigm, pERK expression in one of the parallel circuits, consisting of γm neurons, was progressively inhibited via dopamine. This inhibition resulted in reduced pERK expression in a postsynaptic GABAergic neuron that, in turn, led to an increase in pERK expression in a dopaminergic neuron specifically in the later session during spaced training, suggesting that disinhibition of the dopaminergic neuron occurs during spaced training. The dopaminergic neuron was significant for gene expression in the different MB parallel circuits consisting of α/βs neurons for memory consolidation. Our results suggest that the spacing effect-generating neurons and the neurons engaged in memory reside in the distinct MB parallel circuits and that the spacing effect can be a consequence of evolved neural circuit architecture.
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Gaggi, Giulia, Andrea Di Credico, Pascal Izzicupo, Francesco Alviano, Michele Di Mauro, Angela Di Baldassarre, and Barbara Ghinassi. "Human Mesenchymal Stromal Cells Unveil an Unexpected Differentiation Potential toward the Dopaminergic Neuronal Lineage." International Journal of Molecular Sciences 21, no. 18 (September 9, 2020): 6589. http://dx.doi.org/10.3390/ijms21186589.
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Degeneration of dopaminergic neurons represents the cause of many neurodegenerative diseases, with increasing incidence worldwide. The replacement of dead cells with new healthy ones may represent an appealing therapeutic approach to these pathologies, but currently, only pluripotent stem cells can generate dopaminergic neurons with high efficiency. However, with the use of these cells arises safety and/or ethical issues. Human mesenchymal stromal cells (hFM-MSCs) are perinatal stem cells that can be easily isolated from the amniochorionic membrane after delivery. Generally considered multipotent, their real differentiative potential is not completely elucidated. The aim of this study was to analyze their stemness characteristics and to evaluate whether they may overcome their mesenchymal fate, generating dopaminergic neurons. We demonstrated that hFM-MSCs expressed embryonal genes OCT4, NANOG, SOX2, KLF4, OVOL1, and ESG1, suggesting they have some features of pluripotency. Moreover, hFM-MSCs that underwent a dopaminergic differentiation protocol gradually increased the transcription of dopaminergic markers LMX1b, NURR1, PITX3, and DAT. We finally obtained a homogeneous population of cells resembling the morphology of primary midbrain dopaminergic neurons that expressed the functional dopaminergic markers TH, DAT, and Nurr1. In conclusion, our results suggested that hFM-MSCs retain the expression of pluripotency genes and are able to differentiate not only into mesodermal cells, but also into neuroectodermal dopaminergic neuron-like cells.
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Chen, Yalan, Junxin Kuang, Yimei Niu, Hongyao Zhu, Xiaoxia Chen, Kwok-Fai So, Anding Xu, and Lingling Shi. "Multiple factors to assist human-derived induced pluripotent stem cells to efficiently differentiate into midbrain dopaminergic neurons." Neural Regeneration Research 19, no. 4 (September 4, 2023): 908–14. http://dx.doi.org/10.4103/1673-5374.378203.
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JOURNAL/nrgr/04.03/01300535-202404000-00037/inline-graphic1/v/2023-09-09T133047Z/r/image-tiff Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases. They also represent a potential source of transplanted cells for therapeutic applications. In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development. Emerging evidence and impressive advances in human induced pluripotent stem cells, with tuned neural induction and differentiation protocols, makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible. Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol, we obtained multiple subtypes of neurons, including 20% tyrosine hydroxylase-positive dopaminergic neurons. To obtain more dopaminergic neurons, we next added sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF8) on day 8 of induction. This increased the proportion of dopaminergic neurons, up to 75% tyrosine hydroxylase-positive neurons, with 15% tyrosine hydroxylase and forkhead box protein A2 (FOXA2) co-expressing neurons. We further optimized the induction protocol by applying the small molecule inhibitor, CHIR99021 (CHIR). This helped facilitate the generation of midbrain dopaminergic neurons, and we obtained 31–74% midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining. Thus, we have established three induction protocols for dopaminergic neurons. Based on tyrosine hydroxylase and FOXA2 immunostaining analysis, the CHIR, SHH, and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons, which could be an ideal resource for tackling midbrain-related diseases.
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McDonald, Kirstin O., Nikita M. A. Lyons, Luca K. C. Gray, Janet B. Xu, Lucia Schoderboeck, Stephanie M. Hughes, and Indranil Basak. "Transcription Factor-Mediated Generation of Dopaminergic Neurons from Human iPSCs—A Comparison of Methods." Cells 13, no. 12 (June 11, 2024): 1016. http://dx.doi.org/10.3390/cells13121016.
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Dopaminergic neurons are the predominant brain cells affected in Parkinson’s disease. With the limited availability of live human brain dopaminergic neurons to study pathological mechanisms of Parkinson’s disease, dopaminergic neurons have been generated from human-skin-cell-derived induced pluripotent stem cells. Originally, induced pluripotent stem-cell-derived dopaminergic neurons were generated using small molecules. These neurons took more than two months to mature. However, the transcription-factor-mediated differentiation of induced pluripotent stem cells has revealed quicker and cheaper methods to generate dopaminergic neurons. In this study, we compared and contrasted three protocols to generate induced pluripotent stem-cell-derived dopaminergic neurons using transcription-factor-mediated directed differentiation. We deviated from the established protocols using lentivirus transduction to stably integrate different transcription factors into the AAVS1 safe harbour locus of induced pluripotent stem cells. We used different media compositions to generate more than 90% of neurons in the culture, out of which more than 85% of the neurons were dopaminergic neurons within three weeks. Therefore, from our comparative study, we reveal that a combination of transcription factors along with small molecule treatment may be required to generate a pure population of human dopaminergic neurons.
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Noisa, Parinya, Taneli Raivio, and Wei Cui. "Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons." Stem Cells International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/647437.
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Human embryonic stem cells (hESCs) are able to proliferatein vitroindefinitely without losing their ability to differentiate into multiple cell types upon exposure to appropriate signals. Particularly, the ability of hESCs to differentiate into neuronal subtypes is fundamental to develop cell-based therapies for several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. In this study, we differentiated hESCs to dopaminergic neurons via an intermediate stage, neural progenitor cells (NPCs). hESCs were induced to neural progenitor cells by Dorsomorphin, a small molecule that inhibits BMP signalling. The resulting neural progenitor cells exhibited neural bipolarity with high expression of neural progenitor genes and possessed multipotential differentiation ability. CBF1 and bFGF responsiveness of these hES-NP cells suggested their similarity to embryonic neural progenitor cells. A substantial number of dopaminergic neurons were derived from hES-NP cells upon supplementation of FGF8 and SHH, key dopaminergic neuron inducers. Importantly, multiple markers of midbrain neurons were detected, includingNURR1, PITX3, andEN1, suggesting that hESC-derived dopaminergic neurons attained the midbrain identity. Altogether, this work underscored the generation of neural progenitor cells that retain the properties of embryonic neural progenitor cells. These cells will serve as an unlimited source for the derivation of dopaminergic neurons, which might be applicable for treating patients with Parkinson’s disease.
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Reumann, Daniel, Christian Krauditsch, Maria Novatchkova, Edoardo Sozzi, Sakurako Nagumo Wong, Michael Zabolocki, Marthe Priouret, et al. "In vitro modeling of the human dopaminergic system using spatially arranged ventral midbrain–striatum–cortex assembloids." Nature Methods 20, no. 12 (December 2023): 2034–47. http://dx.doi.org/10.1038/s41592-023-02080-x.
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AbstractVentral midbrain dopaminergic neurons project to the striatum as well as the cortex and are involved in movement control and reward-related cognition. In Parkinson’s disease, nigrostriatal midbrain dopaminergic neurons degenerate and cause typical Parkinson’s disease motor-related impairments, while the dysfunction of mesocorticolimbic midbrain dopaminergic neurons is implicated in addiction and neuropsychiatric disorders. Study of the development and selective neurodegeneration of the human dopaminergic system, however, has been limited due to the lack of an appropriate model and access to human material. Here, we have developed a human in vitro model that recapitulates key aspects of dopaminergic innervation of the striatum and cortex. These spatially arranged ventral midbrain–striatum–cortical organoids (MISCOs) can be used to study dopaminergic neuron maturation, innervation and function with implications for cell therapy and addiction research. We detail protocols for growing ventral midbrain, striatal and cortical organoids and describe how they fuse in a linear manner when placed in custom embedding molds. We report the formation of functional long-range dopaminergic connections to striatal and cortical tissues in MISCOs, and show that injected, ventral midbrain-patterned progenitors can mature and innervate the tissue. Using these assembloids, we examine dopaminergic circuit perturbations and show that chronic cocaine treatment causes long-lasting morphological, functional and transcriptional changes that persist upon drug withdrawal. Thus, our method opens new avenues to investigate human dopaminergic cell transplantation and circuitry reconstruction as well as the effect of drugs on the human dopaminergic system.
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Werner, Felix-Martin, and Rafael Coveñas. "Comparison of Mono-dopaminergic and Multi-target Pharmacotherapies in Primary Parkinson Syndrome and Assessment Tools to Evaluate Motor and Non-motor Symptoms." Current Drug Therapy 14, no. 2 (August 27, 2019): 124–34. http://dx.doi.org/10.2174/1574885513666181115104137.
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Background:Primary Parkinson syndrome is mostly treated by dopaminergic drugs, while the progression of the disease is not altered. Some non-dopaminergic are available, which are administered only after the Parkinsonian symptoms get worse.Objective:The objective of this review is to give basic results in order to compare a dopaminergic and non-dopaminergic pharmacotherapy in Parkinson’s disease and to control whether the add-on pharmacotherapy with non-dopaminergic drugs can inhibit the progression of the disease.Methods:In primary Parkinson syndrome, the altered activity of classical neurotransmitters and neuropeptides in the extrapyramidal system is summarized and up-dated. Anatomical studies on neural networks in the basal ganglia are mentioned. The direct, motor facilitatory pathway (D1 dopaminergic neurons) from the substantia nigra to the thalamus, via the internal globus pallidus, and the indirect, motor inhibitory pathway via D2 dopaminergic neurons have been considered. These established anatomical pathways have been brought in line with the neural interactions derived from neurotransmitter balances or imbalances. Besides, preclinical and clinical studies of effective non-dopaminergic anti-Parkinsonian drugs are reviewed.Results:It can be hypothesized that glutamatergic neurons enhance dopamine deficiency in the substantia nigra and putamen through an increased presynaptic inhibition mediated by NMDA receptors. In the putamen, 5-HT2A serotonergic neurons counteract D2 dopaminergic neurons and A2A adenosine neurons antagonize D2 dopaminergic neurons by activating glutamatergic neurons, which presynaptically inhibit via subtype 5 of metabotropic glutamatergic receptors, D2 dopaminergic neurons. In the extrapyramidal system, an up-dated neural network, which harmonizes established anatomical pathways with derived neural interactions, is presented. In Parkinson’s disease, a question should be answered, whether a combination of dopaminergic and non-dopaminergic drugs can promote an increased motor and non-motor functioning.Conclusion:A mono-target pharmacotherapy (using only dopaminergic drugs) and a multi-target pharmacotherapy (i.e. by combining dopaminergic and non-dopaminergic drugs) are compared. The alternate administration of dopaminergic and non-dopaminergic anti-Parkinsonian drugs, administered at different times during the day, must be tested in order to inhibit the progression of the disease. Assessment tools can be used to evaluate motor and cognitive functions. Moreover, imaging examination techniques can be also applied to control the course of the disease.
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Gale, Samuel D., and David J. Perkel. "Physiological Properties of Zebra Finch Ventral Tegmental Area and Substantia Nigra Pars Compacta Neurons." Journal of Neurophysiology 96, no. 5 (November 2006): 2295–306. http://dx.doi.org/10.1152/jn.01040.2005.
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The neurotransmitter dopamine plays important roles in motor control, learning, and motivation in mammals and probably other animals as well. The strong dopaminergic projection to striatal regions and more moderate dopaminergic projections to other regions of the telencephalon predominantly arise from midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Homologous dopaminergic cell groups in songbirds project anatomically in a manner that may allow dopamine to influence song learning or song production. The electrophysiological properties of SNc and VTA neurons have not previously been studied in birds. Here we used whole cell recordings in brain slices in combination with tyrosine-hydroxylase immunolabeling as a marker of dopaminergic neurons to determine electrophysiological and pharmacological properties of dopaminergic and nondopaminergic neurons in the zebra finch SNc and VTA. Our results show that zebra finch dopaminergic neurons possess physiological properties very similar to those of mammalian dopaminergic neurons, including broad action potentials, calcium- and apamin-sensitive membrane-potential oscillations underlying pacemaker firing, powerful spike-frequency adaptation, and autoinhibition via D2 dopamine receptors. Moreover, the zebra finch SNc and VTA also contain nondopaminergic neurons with similarities (fast-firing, inhibition by the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO)) and differences (strong h-current that contributes to spontaneous firing) compared with GABAergic neurons in the mammalian SNc and VTA. Our results provide insight into the intrinsic membrane properties that regulate the activity of dopaminergic neurons in songbirds and add to strong evidence for anatomical, physiological, and functional similarities between the dopaminergic systems of mammals and birds.
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de Leeuw, Victoria C., Conny T. M. van Oostrom, Edwin P. Zwart, Harm J. Heusinkveld, and Ellen V. S. Hessel. "Prolonged Differentiation of Neuron-Astrocyte Co-Cultures Results in Emergence of Dopaminergic Neurons." International Journal of Molecular Sciences 24, no. 4 (February 10, 2023): 3608. http://dx.doi.org/10.3390/ijms24043608.
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Dopamine is present in a subgroup of neurons that are vital for normal brain functioning. Disruption of the dopaminergic system, e.g., by chemical compounds, contributes to the development of Parkinson’s disease and potentially some neurodevelopmental disorders. Current test guidelines for chemical safety assessment do not include specific endpoints for dopamine disruption. Therefore, there is a need for the human-relevant assessment of (developmental) neurotoxicity related to dopamine disruption. The aim of this study was to determine the biological domain related to dopaminergic neurons of a human stem cell-based in vitro test, the human neural progenitor test (hNPT). Neural progenitor cells were differentiated in a neuron-astrocyte co-culture for 70 days, and dopamine-related gene and protein expression was investigated. Expression of genes specific for dopaminergic differentiation and functioning, such as LMX1B, NURR1, TH, SLC6A3, and KCNJ6, were increasing by day 14. From day 42, a network of neurons expressing the catecholamine marker TH and the dopaminergic markers VMAT2 and DAT was present. These results confirm stable gene and protein expression of dopaminergic markers in hNPT. Further characterization and chemical testing are needed to investigate if the model might be relevant in a testing strategy to test the neurotoxicity of the dopaminergic system.
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Lobb, Collin J., Charles J. Wilson, and Carlos A. Paladini. "A Dynamic Role for GABA Receptors on the Firing Pattern of Midbrain Dopaminergic Neurons." Journal of Neurophysiology 104, no. 1 (July 2010): 403–13. http://dx.doi.org/10.1152/jn.00204.2010.
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Dopaminergic neurons are subject to a significant background GABAergic input in vivo. The presence of this GABAergic background might be expected to inhibit dopaminergic neuron firing. However, dopaminergic neurons are not all silent but instead fire in single-spiking and burst firing modes. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We find that spontaneous single-spiking is more sensitive to activation of GABA receptors than phasic N-methyl-d-aspartate (NMDA)-mediated burst firing in rat slices (P15–P31). Because tonic activation of GABAA receptors has previously been shown to suppress burst firing in vivo, our results suggest that the activity patterns seen in vivo are the result of a balance between excitatory and inhibitory conductances that interact with the intrinsic pacemaking currents observed in slices. Using the dynamic clamp technique, we applied balanced, constant NMDA and GABAA receptor conductances into dopaminergic neurons in slices. Bursts could be produced by disinhibition (phasic removal of the GABAA receptor conductance), and these bursts had a higher frequency than bursts produced by the same NMDA receptor conductance alone. Phasic increases in the GABAA receptor conductance evoked pauses in firing. In contrast to NMDA receptor, application of constant AMPA and GABAA receptor conductances caused the cell to go into depolarization block. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDA receptor–mediated excitatory inputs, control the firing pattern of dopaminergic neurons.
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Volpicelli, Floriana, Carla Perrone-Capano, Gian Carlo Bellenchi, Luca Colucci-D’Amato, and Umberto di Porzio. "Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration." International Journal of Molecular Sciences 21, no. 11 (June 3, 2020): 3995. http://dx.doi.org/10.3390/ijms21113995.
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The relatively few dopaminergic neurons in the mammalian brain are mostly located in the midbrain and regulate many important neural functions, including motor integration, cognition, emotive behaviors and reward. Therefore, alteration of their function or degeneration leads to severe neurological and neuropsychiatric diseases. Unraveling the mechanisms of midbrain dopaminergic (mDA) phenotype induction and maturation and elucidating the role of the gene network involved in the development and maintenance of these neurons is of pivotal importance to rescue or substitute these cells in order to restore dopaminergic functions. Recently, in addition to morphogens and transcription factors, microRNAs have been identified as critical players to confer mDA identity. The elucidation of the gene network involved in mDA neuron development and function will be crucial to identify early changes of mDA neurons that occur in pre-symptomatic pathological conditions, such as Parkinson’s disease. In addition, it can help to identify targets for new therapies and for cell reprogramming into mDA neurons. In this essay, we review the cascade of transcriptional and posttranscriptional regulation that confers mDA identity and regulates their functions. Additionally, we highlight certain mechanisms that offer important clues to unveil molecular pathogenesis of mDA neuron dysfunction and potential pharmacological targets for the treatment of mDA neuron dysfunction.
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Eyer, Gian-Carlo, Stefano Di Santo, Ekkehard Hewer, Lukas Andereggen, Stefanie Seiler, and Hans Rudolf Widmer. "Co-Expression of Nogo-A in Dopaminergic Neurons of the Human Substantia Nigra Pars Compacta Is Reduced in Parkinson’s Disease." Cells 10, no. 12 (November 30, 2021): 3368. http://dx.doi.org/10.3390/cells10123368.
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Parkinson’s disease is mainly characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Together with the small number, the high vulnerability of the dopaminergic neurons is a major pathogenic culprit of Parkinson’s disease. Our previous findings of a higher survival of dopaminergic neurons in the substantia nigra co-expressing Nogo-A in an animal model of Parkinson’s disease suggested that Nogo-A may be associated with dopaminergic neurons resilience against Parkinson’s disease neurodegeneration. In the present study, we have addressed the expression of Nogo-A in the dopaminergic neurons in the substantia nigra in postmortem specimens of diseased and non-diseased subjects of different ages. For this purpose, in a collaborative effort we developed a tissue micro array (TMA) that allows for simultaneous staining of many samples in a single run. Interestingly, and in contrast to the observations gathered during normal aging and in the animal model of Parkinson’s disease, increasing age was significantly associated with a lower co-expression of Nogo-A in nigral dopaminergic neurons of patients with Parkinson’s disease. In sum, while Nogo-A expression in dopaminergic neurons is higher with increasing age, the opposite is the case in Parkinson’s disease. These observations suggest that Nogo-A might play a substantial role in the vulnerability of dopaminergic neurons in Parkinson’s disease.
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Morozova, Ekaterina O., Maxym Myroshnychenko, Denis Zakharov, Matteo di Volo, Boris Gutkin, Christopher C. Lapish, and Alexey Kuznetsov. "Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting." Journal of Neurophysiology 116, no. 4 (October 1, 2016): 1900–1923. http://dx.doi.org/10.1152/jn.00232.2016.
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In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+ current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.
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Ferrarelli, Leslie K. "YAP supports dopaminergic neurons." Science 357, no. 6353 (August 24, 2017): 768.16–770. http://dx.doi.org/10.1126/science.357.6353.768-p.
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Welberg, Leonie. "Weeding out dopaminergic neurons." Nature Reviews Neuroscience 8, no. 4 (April 2007): 247. http://dx.doi.org/10.1038/nrn2122.
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Huang, Yan, Zhan Liu, Bei-Bei Cao, Yi-Hua Qiu, and Yu-Ping Peng. "Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction." Cellular Physiology and Biochemistry 41, no. 3 (2017): 1240–54. http://dx.doi.org/10.1159/000464388.
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Background/Aims: Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA). Methods: Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP+ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons. Results: Treg cells prevented MPP+-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP+-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP+ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection. Conclusion: Treg cells protect dopaminergic neurons against MPP+ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.
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Henriques, Alexandre, Laura Rouvière, Elodie Giorla, Clémence Farrugia, Bilal El Waly, Philippe Poindron, and Noëlle Callizot. "Alpha-Synuclein: The Spark That Flames Dopaminergic Neurons, In Vitro and In Vivo Evidence." International Journal of Molecular Sciences 23, no. 17 (August 30, 2022): 9864. http://dx.doi.org/10.3390/ijms23179864.
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Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson’s disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies.
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Houlihan, Katherine L., Petros P. Keoseyan, Amber N. Juba, Tigran Margaryan, Max E. Voss, Alexander M. Babaoghli, Justin M. Norris, Greg J. Adrian, Artak Tovmasyan, and Lori M. Buhlman. "Folic Acid Improves Parkin-Null Drosophila Phenotypes and Transiently Reduces Vulnerable Dopaminergic Neuron Mitochondrial Hydrogen Peroxide Levels and Glutathione Redox Equilibrium." Antioxidants 11, no. 10 (October 20, 2022): 2068. http://dx.doi.org/10.3390/antiox11102068.
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Loss-of-function parkin mutations cause oxidative stress and degeneration of dopaminergic neurons in the substantia nigra. Several consequences of parkin mutations have been described; to what degree they contribute to selective neurodegeneration remains unclear. Specific factors initiating excessive reactive oxygen species production, inefficient antioxidant capacity, or a combination are elusive. Identifying key oxidative stress contributors could inform targeted therapy. The absence of Drosophila parkin causes selective degeneration of a dopaminergic neuron cluster that is functionally homologous to the substantia nigra. By comparing observations in these to similar non-degenerating neurons, we may begin to understand mechanisms by which parkin loss of function causes selective degeneration. Using mitochondrially targeted redox-sensitive GFP2 fused with redox enzymes, we observed a sustained increased mitochondrial hydrogen peroxide levels in vulnerable dopaminergic neurons of parkin-null flies. Only transient increases in hydrogen peroxide were observed in similar but non-degenerating neurons. Glutathione redox equilibrium is preferentially dysregulated in vulnerable neuron mitochondria. To shed light on whether dysregulated glutathione redox equilibrium primarily contributes to oxidative stress, we supplemented food with folic acid, which can increase cysteine and glutathione levels. Folic acid improved survival, climbing, and transiently decreased hydrogen peroxide and glutathione redox equilibrium but did not mitigate whole-brain oxidative stress.
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Drobysheva, Daria, Kristen Ameel, Brandon Welch, Esther Ellison, Khan Chaichana, Bryan Hoang, Shilpy Sharma, et al. "An Optimized Method for Histological Detection of Dopaminergic Neurons in Drosophila melanogaster." Journal of Histochemistry & Cytochemistry 56, no. 12 (September 2, 2008): 1049–63. http://dx.doi.org/10.1369/jhc.2008.951137.
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Parkinson's disease (PD) affects >1 million Americans and is marked by the loss of dopaminergic neurons in the substantia nigra. PD has been linked to two causative factors: genetic risks (hereditary PD) and environmental toxins (idiopathic PD). In recent years, considerable effort has been devoted to the development of a Drosophila model of human PD that might be useful for examining the cellular mechanisms of PD pathology by genetic screening. In 2000, Feany and Bender reported a Drosophila model of PD in which transgenic flies expressing human mutant α-synuclein exhibited shortened life spans, dopaminergic losses, Parkinsonian behaviors, and Lewy bodies in surviving dopaminergic neurons. Since then, a number of studies have been published that validate the model or build on it; conversely, a number report an inability to replicate the results and suggest that most protocols for dopaminergic histology underreport the actual numbers of dopaminergic neurons in the insect brain. Here we report the optimization of dopaminergic histology in Drosophila and identification of new dopaminergic neurons, show the remarkable dendritic complexity of these neurons, and provide an updated count of these neurons in adult brains. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
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Braisted, J. E., and P. A. Raymond. "Regeneration of dopaminergic neurons in goldfish retina." Development 114, no. 4 (April 1, 1992): 913–19. http://dx.doi.org/10.1242/dev.114.4.913.
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The conditions necessary to trigger regeneration of dopaminergic neurons were investigated in the goldfish retina. Intraocular injection of 6-hydroxydopamine (6-OHDA) was used to destroy dopaminergic neurons, and neuronal regeneration was monitored by injections of the thymidine analog bromodeoxyuridine (BUdR). Regenerated dopaminergic neurons, (identified by double-labeling with anti-tyrosine hydroxylase and anti-BUdR antibodies) were found within 3 weeks after 2 injections of 0.6 mg/ml 6-OHDA (estimated intraocular concentration), but not after injection of lower doses. All retinas with regenerated dopaminergic neurons also contained other types of regenerated neurons, including cones and ganglion cells, consistent with nuclear counts which revealed non-selective cell loss (34–36%) in both the outer and inner nuclear layers after exposure to the high dose, but not lower doses of 6-OHDA. Regenerated neurons were produced by clusters of dividing neuroepithelial cells probably derived from rod precursors in the outer nuclear layer. These results demonstrate that dopaminergic neurons will not regenerate after they are selectively ablated but only as part of a developmental process that involves generation of multiple cell types.
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Miyazaki, Ikuko, and Masato Asanuma. "Neuron-Astrocyte Interactions in Parkinson’s Disease." Cells 9, no. 12 (December 7, 2020): 2623. http://dx.doi.org/10.3390/cells9122623.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.
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Wei, Zhuang-Yao D., and Ashok K. Shetty. "Treating Parkinson’s disease by astrocyte reprogramming: Progress and challenges." Science Advances 7, no. 26 (June 2021): eabg3198. http://dx.doi.org/10.1126/sciadv.abg3198.
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Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is typified by both motor and nonmotor symptoms. The current medications provide symptomatic relief but do not stimulate the production of new dopaminergic neurons in the substantia nigra. Astrocyte reprogramming has recently received much attention as an avenue for increasing functional dopaminergic neurons in the mouse PD brain. By targeting a microRNA (miRNA) loop, astrocytes in the mouse brain could be reprogrammed into functional dopaminergic neurons. Such in vivo astrocyte reprogramming in the mouse model of PD has successfully added new dopaminergic neurons to the substantia nigra and increased dopamine levels associated with axonal projections into the striatum. This review deliberates the astrocyte reprogramming methods using specific transcription factors and mRNAs and the progress in generating dopaminergic neurons in vivo. In addition, the translational potential, challenges, and potential risks of astrocyte reprogramming for an enduring alleviation of parkinsonian symptoms are conferred.
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Limke, Annette, Gereon Poschmann, Kai Stühler, Patrick Petzsch, Thorsten Wachtmeister, and Anna von Mikecz. "Silica Nanoparticles Disclose a Detailed Neurodegeneration Profile throughout the Life Span of a Model Organism." Journal of Xenobiotics 14, no. 1 (January 12, 2024): 135–53. http://dx.doi.org/10.3390/jox14010008.
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The incidence of age-related neurodegenerative diseases is rising globally. However, the temporal sequence of neurodegeneration throughout adult life is poorly understood. To identify the starting points and schedule of neurodegenerative events, serotonergic and dopaminergic neurons were monitored in the model organism C. elegans, which has a life span of 2–3 weeks. Neural morphology was examined from young to old nematodes that were exposed to silica nanoparticles. Young nematodes showed phenotypes such as dendritic beading of serotonergic and dopaminergic neurons that are normally not seen until late life. During aging, neurodegeneration spreads from specifically susceptible ADF and PDE neurons in young C. elegans to other more resilient neurons, such as dopaminergic CEP in middle-aged worms. Investigation of neurodegenerative hallmarks and animal behavior revealed a temporal correlation with the acceleration of neuromuscular defects, such as internal hatch in 2-day-old C. elegans. Transcriptomics and proteomics of young worms exposed to nano silica showed a change in gene expression concerning the gene ontology groups serotonergic and dopaminergic signaling as well as neuropeptide signaling. Consistent with this, reporter strains for nlp-3, nlp-14 and nlp-21 confirmed premature degeneration of the serotonergic neuron HSN and other neurons in young C. elegans. The results identify young nematodes as a vulnerable age group for nano silica-induced neural defects with a significantly reduced health span. Neurodegeneration of specific neurons impairs signaling by classical neurotransmitters as well as neuropeptides and compromises related neuromuscular behaviors in critical phases of life, such as the reproductive phase.
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Guatteo, Ezia, Nicola Berretta, Vincenzo Monda, Ada Ledonne, and Nicola Biagio Mercuri. "Pathophysiological Features of Nigral Dopaminergic Neurons in Animal Models of Parkinson’s Disease." International Journal of Molecular Sciences 23, no. 9 (April 19, 2022): 4508. http://dx.doi.org/10.3390/ijms23094508.
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The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson’s disease (PD), and it is triggered by different factors, including mitochondrial dysfunction, Lewy body accumulation, neuroinflammation, excitotoxicity and metal accumulation. Despite the extensive literature devoted to unravelling the signalling pathways involved in neuronal degeneration, little is known about the functional impairments occurring in these cells during illness progression. Of course, it is not possible to obtain direct information on the properties of the dopaminergic cells in patients. However, several data are available in the literature reporting changes in the function of these cells in PD animal models. In the present manuscript, we focus on dopaminergic neuron functional properties and summarize shared or peculiar features of neuronal dysfunction in different PD animal models at different stages of the disease in an attempt to design a picture of the functional modifications occurring in nigral dopaminergic neurons during disease progression preceding their eventual death.
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Lindvall, Olle. "Treatment of Parkinson's disease using cell transplantation." Philosophical Transactions of the Royal Society B: Biological Sciences 370, no. 1680 (October 19, 2015): 20140370. http://dx.doi.org/10.1098/rstb.2014.0370.
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The clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue, rich in dopaminergic neurons, in Parkinson's disease (PD) patients show that cell replacement can work and in some cases induce major, long-lasting improvement. However, owing to poor tissue availability, this approach can only be applied in very few patients, and standardization is difficult, leading to wide variation in functional outcome. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation. Importantly, dopaminergic neurons of the correct substantia nigra phenotype can now be generated from human embryonic stem cells in large numbers and standardized preparations, and will soon be ready for application in patients. Also, human induced pluripotent stem cell-derived dopaminergic neurons are being considered for clinical translation. Available data justify moving forward in a responsible way with these dopaminergic neurons, which should be tested, using optimal patient selection, cell preparation and transplantation procedures, in controlled clinical studies.
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Mesman, Simone, and Marten P. Smidt. "Acquisition of the Midbrain Dopaminergic Neuronal Identity." International Journal of Molecular Sciences 21, no. 13 (June 30, 2020): 4638. http://dx.doi.org/10.3390/ijms21134638.
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The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.
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Block, M. L., and J. S. Hong. "Chronic microglial activation and progressive dopaminergic neurotoxicity." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1127–32. http://dx.doi.org/10.1042/bst0351127.
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PD (Parkinson's disease) is characterized by the selective and progressive loss of DA neurons (dopaminergic neurons) in the substantia nigra. Inflammation and activation of microglia, the resident innate immune cell in the brain, have been strongly linked to neurodegenerative diseases, such as PD. Microglia can respond to immunological stimuli and neuronal death to produce a host of toxic factors, including cytokines and ROS (reactive oxygen species). Microglia can also become persistently activated after a single stimulus and maintain the elevated production of both cytokines and ROS, long after the instigating stimulus is gone. Current reports suggest that this chronic microglial activation may be fuelled by either dying/damaged neurons or autocrine and paracrine signals from local glial cells, such as cytokines. Here, we review proposed mechanisms responsible for chronic neuroinflammation and explain the interconnected relationship between deleterious microglial activation, DA neuron damage and neurodegenerative disease.
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Rangasamy, Suresh B., Sridevi Dasarathi, Aparna Nutakki, Shreya Mukherjee, Rohith Nellivalasa, and Kalipada Pahan. "Stimulation of Dopamine Production by Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive." Journal of Alzheimer's Disease Reports 5, no. 1 (April 23, 2021): 295–310. http://dx.doi.org/10.3233/adr-210001.
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Background: Parkinson’s disease (PD) is one of the most important neurodegenerative disorders in human in which recovery of functions could be achieved by improving the survival and function of residual dopaminergic neurons in the substantia nigra pars compacta. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway. Objective: Earlier our laboratory has shown that sodium benzoate (NaB), a metabolite of cinnamon and an FDA-approved drug against urea cycle disorders and glycine encephalopathy, increases neuroprotective molecules and protects dopaminergic neurons in a mouse model of PD. Here, we examined whether NaB could stimulate the production of DA in dopaminergic neurons. Methods: We employed PCR, real-time PCR, western blot, immunostaining, and HPLC to study the signature function of dopaminergic neurons. Locomotor functions were monitored in mice by open-field. Results: NaB increased the mRNA and protein expression of TH to produce DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral feeding of NaB increased the expression of TH in the nigra, upregulated striatal DA, and improved locomotor activities in striatum of normal C57/BL6 and aged A53T-α-syn transgenic mice. Rapid induction of cAMP response element binding (CREB) activation by NaB in dopaminergic neuronal cells and the abrogation of NaB-induced expression of TH by siRNA knockdown of CREB suggest that NaB stimulates the transcription of TH in dopaminergic neurons via CREB. Conclusion: These results indicate a new function of NaB in which it may be beneficial in PD via stimulation of DA production from residual dopaminergic neurons.
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Simon, Christopher, Quan Gan, Premasangery Kathivaloo, Nur Mohamad, Jagadeesh Dhamodharan, Arulmoli Krishnan, Bharathi Sengodan, et al. "Deciduous DPSCs Ameliorate MPTP-Mediated Neurotoxicity, Sensorimotor Coordination and Olfactory Function in Parkinsonian Mice." International Journal of Molecular Sciences 20, no. 3 (January 29, 2019): 568. http://dx.doi.org/10.3390/ijms20030568.
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Parkinson’s disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration.
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Matak, Pavle, Andrija Matak, Sarah Moustafa, Dipendra K. Aryal, Eric J. Benner, William Wetsel, and Nancy C. Andrews. "Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice." Proceedings of the National Academy of Sciences 113, no. 13 (February 29, 2016): 3428–35. http://dx.doi.org/10.1073/pnas.1519473113.
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Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.
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Blokhin, Victor, Alina V. Lavrova, Sergey A. Surkov, Eduard R. Mingazov, Natalia M. Gretskaya, Vladimir V. Bezuglov, and Michael V. Ugrumov. "A New Method for the Visualization of Living Dopaminergic Neurons and Prospects for Using It to Develop Targeted Drug Delivery to These Cells." International Journal of Molecular Sciences 23, no. 7 (March 27, 2022): 3678. http://dx.doi.org/10.3390/ijms23073678.
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This is the first study aiming to develop a method for the long-term visualization of living nigrostriatal dopaminergic neurons using 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine-BODIPY (GBR-BP), the original fluorescent substance, which is a derivative of GBR-12909, a dopamine uptake inhibitor. This method is based on the authors’ hypothesis about the possibility of specifically internalizing into dopaminergic neurons substances with a high affinity for the dopamine transporter (DAT). Using a culture of mouse embryonic mesencephalic and LUHMES cells (human embryonic mesencephalic cells), as well as slices of the substantia nigra of adult mice, we have obtained evidence that GBR-BP is internalized specifically into dopaminergic neurons in association with DAT via a clathrin-dependent mechanism. Moreover, GBR-BP has been proven to be nontoxic. As we have shown in a primary culture of mouse metencephalon, GBR-BP is also specifically internalized into some noradrenergic and serotonergic neurons, but is not delivered to nonmonoaminergic neurons. Our data hold great promise for visualization of dopaminergic neurons in a mixed cell population to study their functioning, and can also be considered a new approach for the development of targeted drug delivery to dopaminergic neurons in pathology, including Parkinson’s disease.
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Alsanie, Walaa F., Majid Alhomrani, Ahmed Gaber, Hamza Habeeballah, Heba A. Alkhatabi, Raed I. Felimban, Sherin Abdelrahman, et al. "The Effects of Prenatal Exposure to Pregabalin on the Development of Ventral Midbrain Dopaminergic Neurons." Cells 11, no. 5 (March 1, 2022): 852. http://dx.doi.org/10.3390/cells11050852.
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Pregabalin is widely used as a treatment for multiple neurological disorders; however, it has been reported to have the potential for misuse. Due to a lack of safety studies in pregnancy, pregabalin is considered the last treatment option for various neurological diseases, such as neuropathic pain. Therefore, pregabalin abuse in pregnant women, even at therapeutic doses, may impair fetal development. We used primary mouse embryonic neurons to investigate whether exposure to pregabalin can impair the morphogenesis and differentiation of ventral midbrain neurons. This study focused on ventral midbrain dopaminergic neurons, as they are responsible for cognition, movement, and behavior. The results showed that pregabalin exposure during early brain development induced upregulation of the dopaminergic progenitor genes Lmx1a and Nurr1 and the mature dopaminergic gene Pitx3. Interestingly, pregabalin had different effects on the morphogenesis of non-dopaminergic ventral midbrain neurons. Importantly, our findings illustrated that a therapeutic dose of pregabalin (10 μM) did not affect the viability of neurons. However, it caused a decrease in ATP release in ventral midbrain neurons. We demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of ventral midbrain dopaminergic neurons. These findings are crucial for clinical consideration of the use of pregabalin during pregnancy.
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Pascale, Emilia, Giuseppina Divisato, Renata Palladino, Margherita Auriemma, Edward Faustine Ngalya, and Massimiliano Caiazzo. "Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease." Biomolecules 10, no. 9 (September 3, 2020): 1269. http://dx.doi.org/10.3390/biom10091269.
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Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson’s disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs—specifically microRNAs and long noncoding RNAs—are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration.
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Chen, Ling, Xuejie Huan, Fengju Jia, Zhen Zhang, Mingxia Bi, Lin Fu, Xixun Du, et al. "Deubiquitylase OTUD3 Mediates Endoplasmic Reticulum Stress through Regulating Fortilin Stability to Restrain Dopaminergic Neurons Apoptosis." Antioxidants 12, no. 4 (March 26, 2023): 809. http://dx.doi.org/10.3390/antiox12040809.
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OTU domain-containing protein 3 (OTUD3) knockout mice exhibited loss of nigral dopaminergic neurons and Parkinsonian symptoms. However, the underlying mechanisms are largely unknown. In this study, we observed that the inositol-requiring enzyme 1α (IRE1α)-induced endoplasmic reticulum (ER) stress was involved in this process. We found that the ER thickness and the expression of protein disulphide isomerase (PDI) were increased, and the apoptosis level was elevated in the dopaminergic neurons of OTUD3 knockout mice. These phenomena were ameliorated by ER stress inhibitor tauroursodeoxycholic acid (TUDCA) treatment. The ratio of p-IRE1α/IRE1α, and the expression of X-box binding protein 1-spliced (XBP1s) were remarkably increased after OTUD3 knockdown, which was inhibited by IRE1α inhibitor STF-083010 treatment. Moreover, OTUD3 regulated the ubiquitination level of Fortilin through binding with the OTU domain. OTUD3 knockdown resulted in a decrease in the interaction ability of IRE1α with Fortilin and finally enhanced the activity of IRE1α. Taken together, we revealed that OTUD3 knockout-induced injury of dopaminergic neurons might be caused by activating IRE1α signaling in ER stress. These findings demonstrated that OTUD3 played a critical role in dopaminergic neuron neurodegeneration, which provided new evidence for the multiple and tissue-dependent functions of OTUD3.
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Braisted, J. E., T. F. Essman, and P. A. Raymond. "Selective regeneration of photoreceptors in goldfish retina." Development 120, no. 9 (September 1, 1994): 2409–19. http://dx.doi.org/10.1242/dev.120.9.2409.
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Previous work has shown that the neural retina in adult goldfish can regenerate. Following retinal damage elicited by surgical or cytotoxic lesions, missing neurons are replaced by foci of proliferating neuroepithelial cells, which previous studies have suggested are derived from rod precursors. In the intact retina, rod precursors proliferate but produce only new rods. The regenerative responses observed previously have involved replacement of neurons in all retinal layers; selective regeneration of specific neuronal types (except for rod photoreceptors) has not been reported. In the experiments described here, we specifically destroyed either cones alone or cones and rods with an argon laser, and we found that both types of photoreceptors regenerated within a few weeks. The amount of cone regeneration varied in proportion to the degree of rod loss. This is the first demonstration of selective regeneration of a specific class of neuron (i.e., cones) in a region of central nervous tissue where developmental production of that class of neuron has ceased. Selective regeneration may be limited to photoreceptors, however, because when dopaminergic neurons in the inner retina were ablated with intraocular injections of 6-hydroxydopamine, in combination with laser lesions that destroyed photoreceptors, the dopaminergic neurons did not regenerate, but the photoreceptors did. These data support previous studies which showed that substantial cell loss is required to trigger regeneration of inner retinal neurons, including dopaminergic neurons. New observations here bring into question the presumption that rod precursors are the only source of neuronal progenitors during the regenerative response. Finally, a model is presented which suggests a possible mechanism for regulating the phenotypic fate of retinal progenitor cells during retinal regeneration.
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Sison, Samantha L., and Allison D. Ebert. "Decreased NAD+ in dopaminergic neurons." Aging 10, no. 4 (April 28, 2018): 526–27. http://dx.doi.org/10.18632/aging.101433.
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Lindvall, Olle. "Dopaminergic neurons for Parkinson's therapy." Nature Biotechnology 30, no. 1 (January 2012): 56–58. http://dx.doi.org/10.1038/nbt.2077.
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Breeze, Robert E. "TRANSPLANTATION OF EMBRYONIC DOPAMINERGIC NEURONS." Neurosurgery 49, no. 3 (September 2001): 575–76. http://dx.doi.org/10.1227/00006123-200109000-00006.
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Bubser, Michael, Jim R. Fadel, Lela L. Jackson, James H. Meador-Woodruff, Deqiang Jing, and Ariel Y. Deutch. "Dopaminergic regulation of orexin neurons." European Journal of Neuroscience 21, no. 11 (June 2005): 2993–3001. http://dx.doi.org/10.1111/j.1460-9568.2005.04121.x.
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Zhu, Meng-Yang. "Noradrenergic Modulation on Dopaminergic Neurons." Neurotoxicity Research 34, no. 4 (March 23, 2018): 848–59. http://dx.doi.org/10.1007/s12640-018-9889-z.
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Kuznetsov, Alexey, Leonid Rubchinsky, Nancy Kopell, and Charles Wilson. "Models of midbrain dopaminergic neurons." Scholarpedia 2, no. 10 (2007): 1812. http://dx.doi.org/10.4249/scholarpedia.1812.
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