scholarly journals Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration

2012 ◽  
Vol 3 ◽  
Author(s):  
Patricia Szot ◽  
Allyn Franklin ◽  
Carl Sikkema ◽  
Charles W. Wilkinson ◽  
Murray A. Raskind
Keyword(s):  
Dopaminergic Neurons ◽  
Striatal Dopamine ◽  
Dopamine Concentration ◽  
Sequential Loss ◽  
Neuronal Number

Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans

2003 ◽  
Vol 18 (1) ◽  
pp. 41-48 ◽  
Author(s):  
Ruediger Hilker ◽  
Juergen Voges ◽  
Mehran Ghaemi ◽  
Ralf Lehrke ◽  
Jobst Rudolf ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
Striatal Dopamine ◽  
Dopamine Concentration ◽  
Deep Brain ◽  
Stimulation Of

scholarly journals Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

2018 ◽  
Author(s):  
Michal Wegrzynowicz ◽  
Dana Bar-On ◽  
Laura Calo’ ◽  
Oleg Anichtchik ◽  
Mariangela Iovino ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Dopaminergic Neurons ◽  
Dopamine Release ◽  
Striatal Dopamine ◽  
Substantia Nigra Pars Compacta ◽  
Motor Deficit ◽  
Promising Therapeutic Approach ◽  
Striatal Dopamine Release

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

Restoration of Dopamine Transporter Density in the Striatum of Fetal Ventral Mesencephalon-Grafted, but not Sham-Grafted, Mptp-Treated Parkinsonian Monkeys

1996 ◽  
Vol 5 (2) ◽  
pp. 315-325 ◽  
Author(s):  
John D. Elsworth ◽  
Mark S. Brittan ◽  
Jane R. Taylor ◽  
John R. Sladek ◽  
Mohammed S. Al-Tikriti ◽  
...  
Keyword(s):  
Caudate Nucleus ◽  
Dopamine Transporter ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Dopamine Depletion ◽  
Ventral Mesencephalon ◽  
Behavioral Recovery ◽  
Dopamine System ◽  
Dopamine Concentration ◽  
Neural Grafting

Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease. Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism. However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species. It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained. In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinner-vated with present techniques. Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates. The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys to investigate these issues. Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys. In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey. No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP-treated groups. In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus. Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen. One graft site in each monkey was examined by dopamine transporter autoradiography. In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters. This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group. These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery.

scholarly journals Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

2016 ◽  
Vol 113 (15) ◽  
pp. E2180-E2188 ◽  
Author(s):  
Paul D. Dodson ◽  
Jakob K. Dreyer ◽  
Katie A. Jennings ◽  
Emilie C. J. Syed ◽  
Richard Wade-Martins ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Striatal Dopamine ◽  
Cell Type ◽  
Spontaneous Movement ◽  
Midbrain Dopaminergic Neurons ◽  
Spontaneous Movements

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.

scholarly journals A Mouse Model of Nigrostriatal Dopaminergic Axonal Degeneration As a Tool for Testing Neuroprotectors

Acta Naturae ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 110-113
Author(s):  
Anna A. Kolacheva ◽  
M. V. Ugrumov
Keyword(s):  
Control Level ◽  
Striatal Dopamine ◽  
Parkinsons Disease ◽  
Dopamine Concentration ◽  
Mptp Treatment ◽  
Terminal Degeneration ◽  
Testing Potential ◽  
Neuroprotective Treatment ◽  
Changes Over Time ◽  
Factor Secretion

Degeneration of nigrostriatal dopaminergic neurons in Parkinsons disease begins from the axonal terminals in the striatum and, then, in retrograde fashion, progresses to the cell bodies in the substantia nigra. Investigation of the dynamics of axonal terminal degeneration may help in the identification of new targets for neuroprotective treatment and be used as a tool for testing potential drugs. We have shown that the degeneration rate of dopaminergic axonal terminals changes over time, and that the striatal dopamine concentration is the most sensitive parameter to the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This model was validated using neuroprotectors with well-known mechanisms of action: the dopamine transporter inhibitor nomifensine and SEMAX peptide that stimulates the secretion of endogenous neurotrophic factors or acts as an antioxidant. Nomifensine was shown to almost completely protect dopaminergic fibers from the toxic effect of MPTP and maintain the striatal dopamine concentration at the control level. However, SEMAX, slightly but reliably, increased striatal dopamine when administered before MPTP treatment, which indicates that it is more effective as an inductor of endogenous neurotrophic factor secretion rather than as an antioxidant.

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