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[PMID]:28467897
[Au] Autor:Zhong P; Hu Z; Jiang H; Yan Z; Feng J
[Ad] Endereço:Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA; Veterans Affairs Western New York Healthcare System, Buffalo, NY 14215, USA.
[Ti] Título:Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations.
[So] Source:Cell Rep;19(5):1033-1044, 2017 May 02.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease.
[Mh] Termos MeSH primário: Dopamina/farmacologia
Neurônios Dopaminérgicos/metabolismo
Potenciais Pós-Sinápticos Excitadores
Mesencéfalo/citologia
Mutação
Doença de Parkinson/metabolismo
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Idoso
Estudos de Casos e Controles
Células Cultivadas
Neurônios Dopaminérgicos/efeitos dos fármacos
Neurônios Dopaminérgicos/fisiologia
Feminino
Seres Humanos
Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Pluripotentes Induzidas/fisiologia
Masculino
Mesencéfalo/metabolismo
Mesencéfalo/fisiopatologia
Meia-Idade
Doença de Parkinson/genética
Doença de Parkinson/fisiopatologia
Receptores de Dopamina D1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Dopamine D1); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (parkin protein); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  2 / 15904 MEDLINE  
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[PMID]:27770832
[Au] Autor:Bjorke B; Shoja-Taheri F; Kim M; Robinson GE; Fontelonga T; Kim KT; Song MR; Mastick GS
[Ad] Endereço:Department of Biology, University of Nevada, Reno, NV, 89557, USA.
[Ti] Título:Contralateral migration of oculomotor neurons is regulated by Slit/Robo signaling.
[So] Source:Neural Dev;11(1):18, 2016 10 22.
[Is] ISSN:1749-8104
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Oculomotor neurons develop initially like typical motor neurons, projecting axons out of the ventral midbrain to their ipsilateral targets, the extraocular muscles. However, in all vertebrates, after the oculomotor nerve (nIII) has reached the extraocular muscle primordia, the cell bodies that innervate the superior rectus migrate to join the contralateral nucleus. This motor neuron migration represents a unique strategy to form a contralateral motor projection. Whether migration is guided by diffusible cues remains unknown. METHODS: We examined the role of Slit chemorepellent signals in contralateral oculomotor migration by analyzing mutant mouse embryos. RESULTS: We found that the ventral midbrain expresses high levels of both Slit1 and 2, and that oculomotor neurons express the repellent Slit receptors Robo1 and Robo2. Therefore, Slit signals are in a position to influence the migration of oculomotor neurons. In Slit 1/2 or Robo1/2 double mutant embryos, motor neuron cell bodies migrated into the ventral midbrain on E10.5, three days prior to normal migration. These early migrating neurons had leading projections into and across the floor plate. In contrast to the double mutants, embryos which were mutant for single Slit or Robo genes did not have premature migration or outgrowth on E10.5, demonstrating a cooperative requirement of Slit1 and 2, as well as Robo1 and 2. To test how Slit/Robo midline repulsion is modulated, we found that the normal migration did not require the receptors Robo3 and CXCR4, or the chemoattractant, Netrin 1. The signal to initiate contralateral migration is likely autonomous to the midbrain because oculomotor neurons migrate in embryos that lack either nerve outgrowth or extraocular muscles, or in cultured midbrains that lacked peripheral tissue. CONCLUSION: Overall, our results demonstrate that a migratory subset of motor neurons respond to floor plate-derived Slit repulsion to properly control the timing of contralateral migration.
[Mh] Termos MeSH primário: Orientação de Axônios
Movimento Celular
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia
Neurônios Motores/fisiologia
Proteínas do Tecido Nervoso/fisiologia
Nervo Oculomotor/crescimento & desenvolvimento
Receptores Imunológicos/fisiologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Membrana/fisiologia
Mesencéfalo/fisiologia
Camundongos
Fatores de Crescimento Neural/fisiologia
Netrina-1
Receptores CXCR4/fisiologia
Transdução de Sinais
Proteínas Supressoras de Tumor/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CXCR4 protein, mouse); 0 (Intercellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (Nerve Growth Factors); 0 (Nerve Tissue Proteins); 0 (Ntn1 protein, mouse); 0 (Receptors, CXCR4); 0 (Receptors, Immunologic); 0 (Robo2 protein, mouse); 0 (Robo3 protein, mouse); 0 (Slit homolog 2 protein); 0 (Slit1 protein, mouse); 0 (Tumor Suppressor Proteins); 0 (roundabout protein); 158651-98-0 (Netrin-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171204
[Lr] Data última revisão:
171204
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


  3 / 15904 MEDLINE  
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[PMID]:29049406
[Au] Autor:Colas JT; Pauli WM; Larsen T; Tyszka JM; O'Doherty JP
[Ad] Endereço:Computation and Neural Systems Program, California Institute of Technology, Pasadena, CA, United States of America.
[Ti] Título:Distinct prediction errors in mesostriatal circuits of the human brain mediate learning about the values of both states and actions: evidence from high-resolution fMRI.
[So] Source:PLoS Comput Biol;13(10):e1005810, 2017 Oct.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prediction-error signals consistent with formal models of "reinforcement learning" (RL) have repeatedly been found within dopaminergic nuclei of the midbrain and dopaminoceptive areas of the striatum. However, the precise form of the RL algorithms implemented in the human brain is not yet well determined. Here, we created a novel paradigm optimized to dissociate the subtypes of reward-prediction errors that function as the key computational signatures of two distinct classes of RL models-namely, "actor/critic" models and action-value-learning models (e.g., the Q-learning model). The state-value-prediction error (SVPE), which is independent of actions, is a hallmark of the actor/critic architecture, whereas the action-value-prediction error (AVPE) is the distinguishing feature of action-value-learning algorithms. To test for the presence of these prediction-error signals in the brain, we scanned human participants with a high-resolution functional magnetic-resonance imaging (fMRI) protocol optimized to enable measurement of neural activity in the dopaminergic midbrain as well as the striatal areas to which it projects. In keeping with the actor/critic model, the SVPE signal was detected in the substantia nigra. The SVPE was also clearly present in both the ventral striatum and the dorsal striatum. However, alongside these purely state-value-based computations we also found evidence for AVPE signals throughout the striatum. These high-resolution fMRI findings suggest that model-free aspects of reward learning in humans can be explained algorithmically with RL in terms of an actor/critic mechanism operating in parallel with a system for more direct action-value learning.
[Mh] Termos MeSH primário: Mapeamento Encefálico/métodos
Corpo Estriado/fisiologia
Rememoração Mental/fisiologia
Mesencéfalo/fisiologia
Modelos Neurológicos
Rede Nervosa/fisiologia
Reforço (Psicologia)
[Mh] Termos MeSH secundário: Adaptação Fisiológica/fisiologia
Simulação por Computador
Seres Humanos
Aumento da Imagem/métodos
Imagem por Ressonância Magnética/métodos
Plasticidade Neuronal/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171020
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005810


  4 / 15904 MEDLINE  
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[PMID]:28911883
[Au] Autor:McWilliams TG; Howard L; Wyatt S; Davies AM
[Ad] Endereço:Division of Molecular Biosciences, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, United Kingdom.
[Ti] Título:TNF superfamily member APRIL enhances midbrain dopaminergic axon growth and contributes to the nigrostriatal projection in vivo.
[So] Source:Exp Neurol;298(Pt A):97-103, 2017 Dec.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have studied the role of the tumor necrosis factor superfamily member APRIL in the development of embryonic mouse midbrain dopaminergic neurons in vitro and in vivo. In culture, soluble APRIL enhanced axon growth during a window of development between E12 and E14 when nigrostriatal axons are growing to their targets in the striatum in vivo. April transcripts were detected in both the striatum and midbrain during this period and at later stages. The axon growth-enhancing effect of APRIL was similar to that of glial cell-derived neurotrophic factor (GDNF), but in contrast to GDNF, APRIL did not promote the survival of midbrain dopaminergic neurons. The effect of APRIL on axon growth was prevented by function-blocking antibodies to one of its receptors, BCMA (TNFRSF13A), but not by function-blocking antibodies to the other APRIL receptor, TACI (TNFRSF13B), suggesting that the effects of APRIL on axon growth are mediated by BCMA. In vivo, there was a significant reduction in the density of midbrain dopaminergic projections to the striatum in April-/- embryos compared with wild type littermates at E14. These findings demonstrate that APRIL is a physiologically relevant factor for the nigrostriatal projection. Given the importance of the degeneration of dopaminergic nigrostriatal connections in the pathogenesis and progression of Parkinson's disease, our findings contribute to our understanding of the factors that establish nigrostriatal integrity.
[Mh] Termos MeSH primário: Axônios/fisiologia
Corpo Estriado/fisiologia
Neurônios Dopaminérgicos/fisiologia
Mesencéfalo/fisiologia
Substância Negra/fisiologia
Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia
[Mh] Termos MeSH secundário: Animais
Axônios/efeitos dos fármacos
Células Cultivadas
Corpo Estriado/efeitos dos fármacos
Neurônios Dopaminérgicos/efeitos dos fármacos
Relação Dose-Resposta a Droga
Mesencéfalo/efeitos dos fármacos
Camundongos
Camundongos Knockout
Substância Negra/efeitos dos fármacos
Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tnfsf13 protein, mouse); 0 (Tumor Necrosis Factor Ligand Superfamily Member 13)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170916
[St] Status:MEDLINE


  5 / 15904 MEDLINE  
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[PMID]:28859110
[Au] Autor:Cook JB; Hendrickson LM; Garwood GM; Toungate KM; Nania CV; Morikawa H
[Ad] Endereço:Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
[Ti] Título:Junk food diet-induced obesity increases D2 receptor autoinhibition in the ventral tegmental area and reduces ethanol drinking.
[So] Source:PLoS One;12(8):e0183685, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Similar to drugs of abuse, the hedonic value of food is mediated, at least in part, by the mesostriatal dopamine (DA) system. Prolonged intake of either high calorie diets or drugs of abuse both lead to a blunting of the DA system. Most studies have focused on DAergic alterations in the striatum, but little is known about the effects of high calorie diets on ventral tegmental area (VTA) DA neurons. Since high calorie diets produce addictive-like DAergic adaptations, it is possible these diets may increase addiction susceptibility. However, high calorie diets consistently reduce psychostimulant intake and conditioned place preference in rodents. In contrast, high calorie diets can increase or decrease ethanol drinking, but it is not known how a junk food diet (cafeteria diet) affects ethanol drinking. In the current study, we administered a cafeteria diet consisting of bacon, potato chips, cheesecake, cookies, breakfast cereals, marshmallows, and chocolate candies to male Wistar rats for 3-4 weeks, producing an obese phenotype. Prior cafeteria diet feeding reduced homecage ethanol drinking over 2 weeks of testing, and transiently reduced sucrose and chow intake. Importantly, cafeteria diet had no effect on ethanol metabolism rate or blood ethanol concentrations following 2g/kg ethanol administration. In midbrain slices, we showed that cafeteria diet feeding enhances DA D2 receptor (D2R) autoinhibition in VTA DA neurons. These results show that junk food diet-induced obesity reduces ethanol drinking, and suggest that increased D2R autoinhibition in the VTA may contribute to deficits in DAergic signaling and reward hypofunction observed with obesity.
[Mh] Termos MeSH primário: Dieta Hiperlipídica/efeitos adversos
Neurônios Dopaminérgicos/metabolismo
Obesidade/metabolismo
Receptores de Dopamina D2/metabolismo
[Mh] Termos MeSH secundário: Consumo de Bebidas Alcoólicas/metabolismo
Animais
Dopamina/metabolismo
Neurônios Dopaminérgicos/patologia
Etanol/efeitos adversos
Seres Humanos
Mesencéfalo/metabolismo
Obesidade/etiologia
Obesidade/patologia
Ratos
Área Tegmentar Ventral/metabolismo
Área Tegmentar Ventral/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Dopamine D2); 3K9958V90M (Ethanol); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0183685


  6 / 15904 MEDLINE  
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[PMID]:28858290
[Au] Autor:Nolbrant S; Heuer A; Parmar M; Kirkeby A
[Ad] Endereço:Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
[Ti] Título:Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation.
[So] Source:Nat Protoc;12(9):1962-1979, 2017 Sep.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Generation of precisely patterned neural cells from human pluripotent stem cells (hPSCs) is instrumental in developing disease models and stem cell therapies. Here, we provide a detailed 16-d protocol for obtaining high-purity ventral midbrain (VM) dopamine (DA) progenitors for intracerebral transplantation into animal models and for in vitro maturation into neurons. We have successfully transplanted such cells into the rat; however, in principle, the cells can be used for transplantation into any animal model, and the protocol is designed to also be compatible with clinical transplantation into humans. We show how to precisely set the balance of patterning factors to obtain specifically the caudal VM progenitors that give rise to DA-rich grafts. By specifying how to perform quality control (QC), troubleshooting and adaptation of the procedure, this protocol will facilitate implementation in different laboratories and with a variety of hPSC lines. To facilitate reproducibility of experiments and enable shipping of cells between centers, we present a method for cryopreservation of the progenitors for subsequent direct transplantation or terminal differentiation into DA neurons. This protocol is free of xeno-derived products and can be performed under good manufacturing practice (GMP) conditions.
[Mh] Termos MeSH primário: Neurônios Dopaminérgicos
Células-Tronco Embrionárias/citologia
Mesencéfalo/cirurgia
Transplante de Células-Tronco
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Engenharia Celular
Linhagem Celular
Neurônios Dopaminérgicos/química
Neurônios Dopaminérgicos/citologia
Neurônios Dopaminérgicos/transplante
Perfilação da Expressão Gênica
Seres Humanos
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.078


  7 / 15904 MEDLINE  
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[PMID]:28847807
[Au] Autor:Wu S; Fagan RR; Uttamapinant C; Lifshitz LM; Fogarty KE; Ting AY; Melikian HE
[Ad] Endereço:Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604.
[Ti] Título:The Dopamine Transporter Recycles via a Retromer-Dependent Postendocytic Mechanism: Tracking Studies Using a Novel Fluorophore-Coupling Approach.
[So] Source:J Neurosci;37(39):9438-9452, 2017 Sep 27.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Presynaptic reuptake, mediated by the dopamine (DA) transporter (DAT), terminates DAergic neurotransmission and constrains extracellular DA levels. Addictive and therapeutic psychostimulants inhibit DA reuptake and multiple DAT coding variants have been reported in patients with neuropsychiatric disorders. These findings underscore that DAT is critical for DA neurotransmission and homeostasis. DAT surface availability is regulated acutely by endocytic trafficking, and considerable effort has been directed toward understanding mechanisms that govern DAT's plasma membrane expression and postendocytic fate. Multiple studies have demonstrated DAT endocytic recycling and enhanced surface delivery in response to various stimuli. Paradoxically, imaging studies have not detected DAT targeting to classic recycling endosomes, suggesting that internalized DAT targets to either degradation or an undefined recycling compartment. Here, we leveraged PRIME ( obe ncorporation ediated by nzyme) labeling to couple surface DAT directly to fluorophore, and tracked DAT's postendocytic itinerary in immortalized mesencephalic cells. Following internalization, DAT robustly targeted to retromer-positive endosomes, and DAT/retromer colocalization was observed in male mouse dopaminergic somatodendritic and terminal regions. Short hairpin RNA-mediated Vps35 knockdown revealed that DAT endocytic recycling requires intact retromer. DAT also targeted rab7-positive endosomes with slow, linear kinetics that were unaffected by either accelerating DAT internalization or binding a high-affinity cocaine analog. However, cocaine increased DAT exit from retromer-positive endosomes significantly. Finally, we found that the DAT carboxy-terminal PDZ-binding motif was required for DAT recycling and exit from retromer. These results define the DAT recycling mechanism and provide a unifying explanation for previous, seemingly disparate, DAT endocytic trafficking findings. The neuronal dopamine (DA) transporter (DAT) recaptures released DA and modulates DAergic neurotransmission, and a number of DAT coding variants have been reported in several DA-related disorders, including infantile parkinsonism, attention-deficit/hyperactivity disorder and autism spectrum disorder. DAT is also competitively inhibited by psychostimulants with high abuse potential. Therefore, mechanisms that acutely affect DAT availability will likely exert significant impact on both normal and pathological DAergic homeostasis. Here, we explore the cellular mechanisms that acutely control DAT surface expression. Our results reveal the intracellular mechanisms that mediate DAT endocytic recycling following constitutive and regulated internalization. In addition to shedding light on this critical process, these findings resolve conflict among multiple, seemingly disparate, previous reports on DAT's postendocytic fate.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo
Endocitose
[Mh] Termos MeSH secundário: Animais
Membrana Celular/metabolismo
Proteínas da Membrana Plasmática de Transporte de Dopamina/química
Endossomos/metabolismo
Células HEK293
Seres Humanos
Masculino
Mesencéfalo/citologia
Camundongos
Camundongos Endogâmicos C57BL
Neurônios/metabolismo
Terminações Pré-Sinápticas/metabolismo
Sinais Direcionadores de Proteínas
Transporte Proteico
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Dopamine Plasma Membrane Transport Proteins); 0 (Protein Sorting Signals)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170830
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3885-16.2017


  8 / 15904 MEDLINE  
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[PMID]:28823729
[Au] Autor:Aguilar JI; Dunn M; Mingote S; Karam CS; Farino ZJ; Sonders MS; Choi SJ; Grygoruk A; Zhang Y; Cela C; Choi BJ; Flores J; Freyberg RJ; McCabe BD; Mosharov EV; Krantz DE; Javitch JA; Sulzer D; Sames D; Rayport S; Freyberg Z
[Ad] Endereço:Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
[Ti] Título:Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT.
[So] Source:Neuron;95(5):1074-1088.e7, 2017 Aug 30.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Neurônios/metabolismo
Vesículas Sinápticas/metabolismo
Proteína Vesicular 2 de Transporte de Glutamato/fisiologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Dextroanfetamina/farmacologia
Drosophila
Proteínas de Drosophila/metabolismo
Concentração de Íons de Hidrogênio
Locomoção/efeitos dos fármacos
Mesencéfalo/metabolismo
Camundongos
Neurônios/fisiologia
Terminações Pré-Sinápticas/metabolismo
Proteína Vesicular 2 de Transporte de Glutamato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Vesicular Glutamate Transport Protein 2); TZ47U051FI (Dextroamphetamine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE


  9 / 15904 MEDLINE  
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[PMID]:28821646
[Au] Autor:Minert A; Yatziv SL; Devor M
[Ad] Endereço:Department of Cell and Developmental Biology, Institute of Life Sciences, and Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
[Ti] Título:Location of the Mesopontine Neurons Responsible for Maintenance of Anesthetic Loss of Consciousness.
[So] Source:J Neurosci;37(38):9320-9331, 2017 Sep 20.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The transition from wakefulness to general anesthesia is widely attributed to suppressive actions of anesthetic molecules distributed by the systemic circulation to the cerebral cortex (for amnesia and loss of consciousness) and to the spinal cord (for atonia and antinociception). An alternative hypothesis proposes that anesthetics act on one or more brainstem or diencephalic nuclei, with suppression of cortex and spinal cord mediated by dedicated axonal pathways. Previously, we documented induction of an anesthesia-like state in rats by microinjection of small amounts of GABA -receptor agonists into an upper brainstem region named the mesopontine tegmental anesthesia area (MPTA). Correspondingly, lesioning this area rendered animals resistant to systemically delivered anesthetics. Here, using rats of both sexes, we applied a modified microinjection method that permitted localization of the anesthetic-sensitive neurons with much improved spatial resolution. Microinjected at the MPTA hotspot identified, exposure of 1900 or fewer neurons to muscimol was sufficient to sustain whole-body general anesthesia; microinjection as little as 0.5 mm off-target did not. The GABAergic anesthetics pentobarbital and propofol were also effective. The GABA-sensitive cell cluster is centered on a tegmental (reticular) field traversed by fibers of the superior cerebellar peduncle. It has no specific nuclear designation and has not previously been implicated in brain-state transitions. General anesthesia permits pain-free surgery. Furthermore, because anesthetic agents have the unique ability to reversibly switch the brain from wakefulness to a state of unconsciousness, knowing how and where they work is a potential route to unraveling the neural mechanisms that underlie awareness itself. Using a novel method, we have located a small, and apparently one of a kind, cluster of neurons in the mesopontine tegmentum that are capable of effecting brain-state switching when exposed to GABA -receptor agonists. This action appears to be mediated by a network of dedicated axonal pathways that project directly and/or indirectly to nearby arousal nuclei of the brainstem and to more distant targets in the forebrain and spinal cord.
[Mh] Termos MeSH primário: Anestésicos Gerais/administração & dosagem
Mesencéfalo/efeitos dos fármacos
Ponte/efeitos dos fármacos
Ponte/fisiologia
Inconsciência/induzido quimicamente
Inconsciência/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Muscimol/administração & dosagem
Neurônios/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, General); 2763-96-4 (Muscimol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0544-17.2017


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[PMID]:28800615
[Au] Autor:Kouwenhoven WM; von Oerthel L; Smidt MP
[Ad] Endereço:Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
[Ti] Título:Pitx3 and En1 determine the size and molecular programming of the dopaminergic neuronal pool.
[So] Source:PLoS One;12(8):e0182421, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral midbrain. These neurons form the substantia nigra (SNc) and the ventral tegmental area (VTA). Two transcription factors that play important roles in the process of terminal differentiation and subset-specification of mdDA neurons, are paired-like homeodomain transcription factor 3 (Pitx3), and homeobox transcription factor Engrailed 1 (En1). We previously investigated the single Pitx3KO and En1KO and observed important changes in the survival of mdDA neurons of the SNc and VTA as well as altered expression of pivotal rostral- and caudal-markers, Ahd2 and Cck, respectively. To refine our understanding of the regional-specific relationships between En1 and Pitx3 and their (combined) role in the programming mdDA neurons on the rostral-to-caudal axis, we created double En1tm1Alj/tm1Alj;Pitx3gfp/gfp (En1KO;Pitx3GFP/GFP) animals. Here we report, that in absence of En1 and Pitx3, only a limited number of mdDA neurons are present at E14.5. These mdDA neurons have a rudimentary dopaminergic cell fate, as they express Nurr1, Pbx3 and Otx2 but have lost their rostral or caudal subset identity. Furthermore, we report that the expression of Cck depends on En1 expression, while (in contrast) both Pitx3 and En1 are involved in the initiation of Ahd2 expression. Thus we reveal in this manuscript that regulated levels of Pitx3 and En1 control the size and rostral/caudal-identity of the mdDA neuronal population.
[Mh] Termos MeSH primário: Reprogramação Celular
Neurônios Dopaminérgicos/citologia
Neurônios Dopaminérgicos/metabolismo
Proteínas de Homeodomínio/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Cruzamento
Sobrevivência Celular
Embrião de Mamíferos/metabolismo
Feminino
Proteínas de Fluorescência Verde/metabolismo
Masculino
Mesencéfalo/citologia
Camundongos
Mutação/genética
Reação em Cadeia da Polimerase
Tirosina 3-Mono-Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (En1 protein, mouse); 0 (Homeodomain Proteins); 0 (Transcription Factors); 0 (homeobox protein PITX3); 147336-22-9 (Green Fluorescent Proteins); EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182421



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