scholarly journals Mechanism of manganese dysregulation of dopamine neuronal activity

2019 ◽  
Author(s):  
Min Lin ◽  
Luis M. Colon-Perez ◽  
Danielle O. Sambo ◽  
Douglas R. Miller ◽  
Joseph J. Lebowitz ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Action Potentials ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Manganese Exposure ◽  
Physiological Processes ◽  
Rhythmic Firing ◽  
Dopamine Transmission ◽  
Potential Width

AbstractManganese exposure produces Parkinson’s-like neurological symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies suggest manganese accumulates in dopamine neurons of the ventral tegmental area and substantia nigra via nifedipine-sensitive Ca2+ channels. Manganese produces a Ca2+ channel-mediated current which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+ channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.Significance StatementManganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurological disorders such as a Parkinson’s disease-like syndrome known as manganism. We found manganese dose-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca2+ channels prevented these effects as well as manganese accumulation in the mouse midbrain in vivo. Our data provide a potential mechanism for manganese-regulation of dopaminergic neurons.

scholarly journals Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

2018 ◽  
Author(s):  
Soledad Marton ◽  
Bruno González ◽  
Sebastián Rodríguez ◽  
Ernesto Miquel ◽  
Laura Martínez Palma ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Acute Administration ◽  
Dependent Manner ◽  
Self Administration ◽  
Seeking Behavior ◽  
A Site ◽  
Dose Dependent

<p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p>

scholarly journals Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

2018 ◽  
Author(s):  
Markus Riessland ◽  
Benjamin Kolisnyk ◽  
Tae Wan Kim ◽  
Jia Cheng ◽  
Jason Ni ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cellular Senescence ◽  
Dopaminergic Neurons ◽  
Dna Binding Protein ◽  
Dopamine Neurons ◽  
Human Stem Cell ◽  
Transcriptional Program

AbstractCellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson‘s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson’s disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson’s disease.

scholarly journals Dopamine transporter is a master regulator of dopaminergic neural network connectivity

2021 ◽  
Author(s):  
Douglas Miller ◽  
Dylan T. Guenther ◽  
Andrew P. Maurer ◽  
Carissa A. Hansen ◽  
Andrew Zalesky ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
Dopaminergic Neurons ◽  
D2 Receptor ◽  
Neuronal Loss ◽  
Network Connectivity ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Differential Sensitivity ◽  
Network Clustering ◽  
Whole Cell Patch Clamp

AbstractDopaminergic neurons of the substantia nigra (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here we utilized live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC dopamine neurons than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC, or VTA networks. Neuronal loss in the SNC decreased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by increasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.

Physiological Properties of Macaque V1 Neurons are Correlated With Extracellular Spike Amplitude, Duration, and Polarity

1999 ◽  
Vol 82 (3) ◽  
pp. 1451-1464 ◽  
Author(s):  
Moshe Gur ◽  
Alexander Beylin ◽  
D. Max Snodderly
Keyword(s):  
Cell Size ◽  
Action Potentials ◽  
Functional Organization ◽  
Brain Regions ◽  
Small Cells ◽  
Cortical Layers ◽  
Stimulus Motion ◽  
V1 Neurons ◽  
Physiological Properties

In the lateral geniculate nucleus (LGN) the large neurons of the magnocellular layers are functionally distinct and anatomically segregated from the small neurons of the parvocellular layers. This segregation of large and small cells is not maintained in the primary visual cortex (V1); instead a heterogeneous mixture of cells occurs, particularly in the output layers. Nevertheless, our results indicate that for the middle and upper layers of V1, cell size remains a predictor of physiological properties. We recorded extracellularly from neurons in V1 of alert monkeys and analyzed the amplitude, duration, and polarity of the action potentials of 199 cells. Of 156 cells that could be assigned to specific cortical layers, 137 (88%) were localized to the middle and upper cortical layers, layer 4 and above. We summarize evidence that the large-amplitude spikes are discharged by large cells, whereas small-amplitude spikes are the action potentials of smaller cells. Large spikes were predominantly negative and of longer duration, whereas small spikes were predominantly positive and briefer. The putative large cells had lower ongoing activity, smaller receptive field activating regions and higher selectivity for stimulus geometry and stimulus motion than the small cells. The contrasting properties of the large and the small cells were illustrated dramatically in simultaneous recordings made from adjacent cells. Our results imply that there may be an anatomic pairing or clustering of small and large cells that could be integral to the functional organization of the cortex. We suggest that the small and the large cells of area V1 have different roles, such that the small cells may shape the properties of the large output cells. If some of the small cells are also output cells, then cell size should be a predictor of the type of information being sent to other brain regions. Because of their high activity and relative ease of stimulation, the small cells also may contribute disproportionately to in vivo images based on metabolic responses such as changes in blood flow.

scholarly journals A Modeling Study Suggesting a Possible Pharmacological Target to Mitigate the Effects of Ethanol on Reward-Related Dopaminergic Signaling

2008 ◽  
Vol 99 (5) ◽  
pp. 2703-2707 ◽  
Author(s):  
Michele Migliore ◽  
Claudio Cannia ◽  
Carmen C. Canavier
Keyword(s):  
Dopaminergic Neurons ◽  
Temporal Structure ◽  
Ionic Current ◽  
Brain Regions ◽  
Point Of View ◽  
Dopamine Level ◽  
Addictive Behaviors ◽  
Brain Functions

Midbrain dopaminergic neurons are involved in several critical brain functions controlling goal-directed behaviors, reinforcing/reward processes, and motivation. Their dysfunctions alter dopamine release and contribute to a vast range of neural disorders, from Parkinson's disease to schizophrenia and addictive behaviors. These neurons have thus been a natural target of pharmacological treatments trying to ameliorate the consequences of several neuropathologies. From this point of view, a clear experimental link has been recently established between the increase in the pacemaker frequency of dopaminergic neurons in vitro after acute ethanol application and a particular ionic current ( Ih). The functional consequences in vivo, however, are not clear and they are very difficult to explore experimentally. Here we use a realistic computational model of dopaminergic neurons in vivo to suggest that ethanol, through its effects on Ih, modifies the temporal structure of the spiking activity. The model predicts that the dopamine level may increase much more during bursting than during pacemaking activity, especially in those brain regions with a slow dopamine clearance rate. The results suggest that a selective pharmacological remedy could thus be devised against the rewarding effects of ethanol that are postulated to mediate alcohol abuse and addiction, targeting the specific HCN genes expressed in dopaminergic neurons.

Arrhythmic Firing in Dopamine Neurons of Rat Substantia Nigra Evoked by Activation of Subthalamic Neurons

1999 ◽  
Vol 82 (3) ◽  
pp. 1632-1637 ◽  
Author(s):  
Youngnam Kang ◽  
Takahiro Futami
Keyword(s):  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Interspike Interval ◽  
Dopamine Neurons ◽  
Low Threshold ◽  
Rhythmic Firing ◽  
Subthalamic Neurons ◽  
Synaptic Influence ◽  
Rat Substantia Nigra

Intracellular recordings were made from dopaminergic neurons of the rat substantia nigra compacta (SNc) in in vitro slice preparations to study the synaptic influence from the subthalamic nucleus (STh). After microstimulation of STh, monosynaptic excitatory postsynaptic potentials (EPSPs) were produced in dopaminergic neurons. STh-induced EPSPs were composed of 6-cyano-7-nitroquinoxalene-2,3-dione- and 2-amino-5-phosphonovaleric acid-sensitive components. Subthreshold EPSPs evoked by STh stimulation could differentially trigger pacemaker-like slow depolarization (PLSD) and low-threshold Ca2+ spike (LTS) depending on the level of baseline membrane potentials. When a subthreshold EPSP was evoked by STh stimulation during rhythmic firing, the STh-induced EPSP could shift or elevate PLSD to a more depolarized level, resulting in generation of a spike at an earlier arrhythmic timing to restart the rhythmic firing. The interspike interval after the arrhythmic spike remained almost unchanged. In contrast, when a suprathreshold EPSP for evoking spikes was produced by STh stimulation during rhythmic firing, the STh-induced spike was just interposed between two spontaneous spikes the interspike interval of which was almost the same as those seen during the preceding rhythmic firing. This ectopically induced spike did not disturb or reset rhythmic firing. It was concluded that SNc dopaminergic neurons receive monosynaptic glutamatergic inputs from STh, and subthreshold and suprathreshold EPSPs evoked by STh stimulations can induce two types of arrhythmic firing in SNc dopaminergic neurons, similar to arrhythmic occurrences of the QRS complex seen in the electrocardiogram of the atrial and ventricular arrhythmias, respectively. The former arrhythmic firing may play a crucial role in desynchronization of dopaminergic neurons.

Hyperlocomotion during Recovery from Isoflurane Anesthesia Is Associated with Increased Dopamine Turnover in the Nucleus Accumbens and Striatum in Mice

1997 ◽  
Vol 86 (2) ◽  
pp. 464-475 ◽  
Author(s):  
Masahiro Irifune ◽  
Tomoaki Sato ◽  
Takashige Nishikawa ◽  
Takashi Masuyama ◽  
Masahiro Nomoto ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Nucleus Accumbens ◽  
High Performance ◽  
Gas Flow ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Dopamine Turnover

Background It was recently reported that isoflurane increases dopamine release in the striatum in rats both in vivo and in vitro, and that isoflurane inhibits uptake of dopamine in the rat brain synaptosomes. However, the functional role of these effects of isoflurane on dopamine neurons is uncertain. Dopaminergic mechanisms within the nucleus accumbens and striatum play an important role in the control of locomotor activity, and a change in dopamine turnover depends essentially on a change in impulse flow in the dopamine neurons. In this study, the effects of isoflurane on locomotor activity and on dopamine turnover were investigated in discrete brain regions in mice. Methods Mice were placed in individual airtight clear plastic chambers and spontaneously breathed isoflurane in 25% oxygen and 75% nitrogen (fresh gas flow, 4 l/min). Locomotor activity was measured with an Animex activity meter. Animals were decapitated after treatments with or without isoflurane, and the concentrations of monoamines and their metabolites in different brain areas were measured by high-performance liquid chromatography. Results During the 10 min after the cessation of the 20-min exposure to isoflurane, there was a significant increase in locomotor activity in animals breathing 1.5% isoflurane but not 0.7% isoflurane. This increase in locomotor activity produced by 1.5% isoflurane was abolished by a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist. Regional brain monoamine assays revealed that 1.5% isoflurane significantly increased the 3,4-dihydroxyphenylacetic acid:dopamine ratio (one indicator of transmitter turnover) in the nucleus accumbens and striatum, but a concentration of 0.7% did not. This significant increase in dopamine turnover in these regions continued during 20 min after the cessation of the administration of 1.5% isoflurane. Conclusions These results suggest that isoflurane-induced hyperlocomotion during emergence may be associated with increased dopamine turnover in the nucleus accumbens and striatum.

scholarly journals The Emerging Role of Neuropeptides in Parkinson’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Yanan Zheng ◽  
Linlin Zhang ◽  
Junxia Xie ◽  
Limin Shi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Age Related ◽  
Pituitary Adenylate Cyclase ◽  
New Strategy

Parkinson’s disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several in vitro and in vivo studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.

scholarly journals Neurodegeneration caused by LRRK2-G2019S requires Rab10 in select dopaminergic neurons

2019 ◽  
Author(s):  
Stavroula Petridi ◽  
C. Adam Middleton ◽  
Alison Fellgett ◽  
Laura Covill ◽  
Amy Stewart ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dopamine Neurons ◽  
Rab Gtpases ◽  
Loss Of Function ◽  
Knock Out ◽  
Electrophysiological Responses ◽  
Lrrk2 G2019s ◽  
Inherited Mutations

AbstractInherited mutations in the LRRK2 protein are the commonest known cause of Parkinson’s, but the molecular link from increased kinase activity to pathological neurodegeneration remains to be determined.In vitro(biochemical and cell culture) assays led to the hypothesis that several Rab GTPases might be LRRK2 substrates. Here we show that Rab10 potently modifiesLRRK2-G2019Smediated electrophysiological responses in anin vivoscreen, in which each Rab was overexpressed inDrosophiladopaminergic neurons. We therefore tested the effect ofRab10loss of function on threeLRRK2-G2019Sphenotypes (vision, movement and sleep) that rely on dopaminergic circuits in both flies and mammals. The knock-out of Rab10in vivofully rescues the reduced responses induced by dopaminergicLRRK2-G2019Sin visual and motor (reaching, proboscis extension) assays, but the sleep phenotype is unaffected. We show that Rab10 is expressed in dopaminergic (tyrosine hydroxylase positive) neurons controlling vision and proboscis movement, but undetectable in those controlling sleep, indicating that anatomical and physiological patterns of Rab10 are related. Our results support the idea that LRRK2 phosphorylates separate targets in distinct neurons and confirm that one degenerative pathway starts with Rab10. Although Rab3 is another putative substrate of LRRK2, it shows no synergy with G2019S and localises to a different subset of dopaminergic neurons from Rab10. We propose that variations inRabexpression may contribute to differences in the rate of neurodegeneration seen in different dopaminergic nuclei in Parkinson’s.Significance StatementA key question in Parkinson’s is why dopamine neurons die particularly fast in some parts of thesubstantia nigra. We focused on the commonest Parkinson’s-related mutation, LRRK2-G2019S.In vitroassays suggested that neurodegeneration may start by LRRK2-G2019S increasing phosphorylation of Rab10. We found Rab10 in fly dopamine neurons in visual and motor pathways, but not in the sleep system. Rab10 knock-out rescues G2019S-induced visual and movement degeneration, leaving sleep dysfunction unaffected. Thus, LRRK2 activates at least two pathways, one Rab10-dependent, leading to neurodegenerationin vivo. Rab3 is found in a different subset of dopaminergic neurons and shows no synergy withLRRK2-G2019S. We propose that variations inRabexpression contribute to differences in neurodegeneration seen in Parkinson’s.

scholarly journals Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits

2018 ◽  
Author(s):  
Soledad Marton ◽  
Bruno González ◽  
Sebastián Rodríguez ◽  
Ernesto Miquel ◽  
Laura Martínez Palma ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Acute Administration ◽  
Dependent Manner ◽  
Self Administration ◽  
Seeking Behavior ◽  
A Site ◽  
Dose Dependent

<p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p>

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