Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Development of Dopaminergic Neurons 3.0

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Related Special Issues
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 24056

Share This Special Issue

Special Issue Editor

Dr. Yasemin M. Akay

E-Mail Website
Guest Editor

Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, USA
Interests: coronary artery disease; stent; noninvasive monitoring; nonlinear dynamics analysis; approximate entropy; 3D co-culture; glioblastoma; astrocytes; tumor microenvironment; PEGDA; addiction; cancer research; data science in medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dopaminergic neurons located in the mammalian ventral midbrain have attracted the attention of many biomedical researchers due to their effect in severe human neuropsychiatric and neurodegenerative disorders. There are four major signalling pathways which play critical roles during the development of the midbrain dopaminergic (mDA) neurons. In spite of the intense research conducted in recent years, we have achieved little understanding related to the crosstalk and the interaction between those four major signalling pathways and how they promote the development of mDA neurons in the mammalian embryo. This has been a very exciting research field and a number of questions remain answering:

(1) Which cellular and molecular mechanisms constitute the basis for the programming of the development of VTA DA neurons versus SNc DA neurons in vivo?

2) What could be the explanation for the vulnerability of some types of mDA neurons in some neurodegenerative disorders?

(3) What will be the efficacy and safety outcomes of the clinical trials using human stem cell-derived mDA neurons?

Contributions to this Special Issue will provide new insights into the mechanisms of action of the development of DA neurons and for the modelling and drug screening of the disorders mentioned above in the basic and clinical research.

Due to the success of the 1st and 2nd editions, we would like to add more results and new insights from recent research projects. You can find the 1st and 2nd editions at the following link:

https://www.mdpi.com/journal/ijms/special_issues/dopaminergic_neurons

https://www.mdpi.com/journal/ijms/special_issues/7WRQJ0EJ04

Dr. Yasemin M. Akay
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neuron
dopamine
mDA
signalling pathways
human stem cell

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Related Special Issues

Development of Dopaminergic Neurons, 4th Edition in International Journal of Molecular Sciences
Development of Dopaminergic Neurons in International Journal of Molecular Sciences (9 articles)
Development of Dopaminergic Neurons 2.0 in International Journal of Molecular Sciences (12 articles)

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

16 pages, 9477 KiB

Open AccessArticle

Localization of Melanocortin 1 Receptor in the Substantia Nigra

by Ayuka Ehara, Nozomi Ito, Kazuhiko Nakadate and Nobuko Tokuda

Int. J. Mol. Sci. 2025, 26(1), 236; https://doi.org/10.3390/ijms26010236 - 30 Dec 2024

Viewed by 786

Abstract

Recent findings have revealed that melanocortin 1 receptor (MC1R) deficiency leads to Parkinson’s disease-like dopaminergic neurodegeneration in the substantia nigra (SN). However, its precise distribution and expressing-cell type in the SN remain unclear. Therefore, in this study, we analyzed the localization and characteristics of MC1R in the SN using histological methods, including in situ hybridization and immunohistochemistry. Our findings reveal that MC1R was slightly present in dopaminergic neurons in the ventral tier of SN pars compacta dorsal (vSNCD), a region particularly vulnerable to PD-related neurodegeneration. Notably, we discovered that MC1R is highly present in parvalbumin (PV)-positive neurons, which were also vesicular GABA transporter messenger RNA-expressing inhibitory neurons of the lateral SN pars reticulata (lSNR). Intracellular analysis demonstrated that MC1R was present not only in the plasma membrane but also in mitochondrial and endoplasmic reticulum membranes. Furthermore, MC1R co-localized with attractin (Atrn), a known MC1R modulator, in nearly all MC1R-positive neurons. Therefore, it has been suggested that MC1R and Atrn work together to regulate dopaminergic neurons in the SN through both direct expression and indirect modulation via PV-positive inhibitory neurons. These findings provide new insights into MC1R’s role in the SN and its potential contribution to PD pathophysiology Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

15 pages, 7064 KiB

Open AccessArticle

Robust In Vitro Models for Studying Parkinson’s Disease? LUHMES Cells and SH-SH5Y Cells

by Cameron Noah Keighron, Sahar Avazzedeh and Leo R. Quinlan

Int. J. Mol. Sci. 2024, 25(23), 13122; https://doi.org/10.3390/ijms252313122 - 6 Dec 2024

Viewed by 1093

Abstract

As our population ages, there is an increased unmet clinical need surrounding neurodegenerative diseases such as Parkinson’s disease (PD). To tackle this ever-increasing problem, we must ensure that the cell models that we use to develop therapeutics in vitro are robust, reliable, and replicable. In this study, we compared SH-SY5Y cells with LUHMES cells in response to 6-Hydroxydopamine (6OHDA) and 1-Methyl-4-phenylpyridinium (MPP+), two common Parkinson’s insults used in in vitro analysis. Both these cell types have apparent dopaminergic phenotypes, which could aid us in understanding their potential in this race to novel therapies. The LUHMES cells showed consistent dopaminergic (DA) expression through tyrosine hydroxylase (TH) positivity, alongside depleted ATP levels and elevated reactive oxygen species (ROS) production, whereas the SH-SH5Y cells displayed resilience to both chemical insults, raising questions about their utility in accurately modelling PD pathology. Further electrophysiological analysis revealed comparable firing rates and ion channel signalling between both cell types; however, LUHMES cells demonstrated stronger calcium signalling responses, further supporting their use as a more robust PD model. While SH-SY5Y cells showed some adaptability in vitro, their inconsistent DA phenotype and limited response to chemical insults limit their suitability for advanced research, suggesting that LUHMES cells should and must take their place as a hallmark in Parkinson’s disease research. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

29 pages, 12472 KiB

Open AccessArticle

A Risk Factor for Attention Deficit Hyperactivity Disorder Induces Marked Long-Term Anatomical Changes at GABAergic-Dopaminergic Synapses in the Rat Ventral Tegmental Area

by Steve Seo, Louise C. Parr-Brownlie, Hollie E. Wicky, David K. Bilkey, Stephanie M. Hughes and Dorothy E. Oorschot

Int. J. Mol. Sci. 2024, 25(23), 12970; https://doi.org/10.3390/ijms252312970 - 2 Dec 2024

Viewed by 1008

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. However, the core biology of the disorder that leads to the hypofunctioning of the cerebral dopaminergic network requires further elucidation. We investigated midbrain synaptic changes in male rats exposed to repeated hypoxia during the equivalent of extreme prematurity, which is a new animal model of the hyperactive/impulsive presentation of ADHD. We used a novel combination of a lentiviral vector, peroxidase-immunonanogold double-labelling, three-dimensional serial section transmission electron microscopy and stereological techniques to investigate the synapses formed between GABAergic axons of the rostromedial tegmental nucleus (RMTg) and dopaminergic neurons of the posterior ventral tegmental area (pVTA). This is a key site that sends extensive dopaminergic projections to the forebrain. We also compared the results to our previous study on a schizophrenia risk factor that produces cerebral hyperdopaminergia. In total, 117 reconstructed synapses were compared. Repeated hypoxic rats had a significantly thicker (22%) and longer (18%) postsynaptic density at RMTg GABAergic-pVTA dopaminergic synapses compared to their controls. These results were opposite to those previously observed in rats exposed to a schizophrenia risk factor. These findings for repeated hypoxic rats suggest that the enhanced inhibition of pVTA dopaminergic neurons may contribute to hypodopaminergia in ADHD motor hyperactivity. Synaptic triads, a key component of pVTA circuitry, were not detected in repeated hypoxic rats, indicating a marked deficit. The current knowledge may guide development in males of novel, site-specific ADHD drugs, which is necessary due to the rising prevalence of ADHD, the chronic nature of ADHD symptoms and the limitations of the currently available medications. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

22 pages, 2583 KiB

Open AccessArticle

Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats

by Cruz Reyes-Vasquez, Zachary Jones, Bin Tang and Nachum Dafny

Int. J. Mol. Sci. 2023, 24(23), 16628; https://doi.org/10.3390/ijms242316628 - 22 Nov 2023

Cited by 1 | Viewed by 3644

Abstract

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1–6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

19 pages, 7243 KiB

Open AccessArticle

In Vitro Human Monoamine Oxidase Inhibition and Human Dopamine D₄ Receptor Antagonist Effect of Natural Flavonoids for Neuroprotection

by Pradeep Paudel, Jae Sue Choi, Ritu Prajapati, Su Hui Seong, Se Eun Park, Woo-Chang Kang, Jong-Hoon Ryu and Hyun Ah Jung

Int. J. Mol. Sci. 2023, 24(21), 15859; https://doi.org/10.3390/ijms242115859 - 1 Nov 2023

Viewed by 2357

Abstract

Natural flavone and isoflavone analogs such as 3′,4′,7-trihydroxyflavone (1), 3′,4′,7-trihydroxyisoflavone (2), and calycosin (3) possess significant neuroprotective activity in Alzheimer’s and Parkinson’s disease. This study highlights the in vitro human monoamine oxidase (hMAO) inhibitory potential and functional effect of those natural flavonoids at dopamine and serotonin receptors for their possible role in neuroprotection. In vitro hMAO inhibition and enzyme kinetics studies were performed using a chemiluminescent assay. The functional effect of three natural flavonoids on dopamine and serotonin receptors was tested via cell-based functional assays followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. A forced swimming test was performed in the male C57BL/6 mouse model. Results of in vitro chemiluminescent assays and enzyme kinetics depicted 1 as a competitive inhibitor of hMAO-A with promising potency (IC₅₀ value: 7.57 ± 0.14 μM) and 3 as a competitive inhibitor of hMAO-B with an IC₅₀ value of 7.19 ± 0.32 μM. Likewise, GPCR functional assays in transfected cells showed 1 as a good hD₄R antagonist. In docking analysis, these active flavonoids interacted with a determinant-interacting residue via hydrophilic and hydrophobic interactions, with low docking scores comparable to reference ligands. The post-oral administration of 1 to male C57BL/6 mice did not reduce the immobility time in the forced swimming test. The results of this study suggest that 1 and 3 may serve as effective regulators of the aminergic system via hMAO inhibition and the hD₄R antagonist effect, respectively, for neuroprotection. The route of administration should be considered. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

27 pages, 7380 KiB

Open AccessArticle

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis

by Diana Alejandra Quintero-Espinosa, Carlos Velez-Pardo and Marlene Jimenez-Del-Rio

Int. J. Mol. Sci. 2023, 24(21), 15744; https://doi.org/10.3390/ijms242115744 - 30 Oct 2023

Cited by 2 | Viewed by 2047

Abstract

Several efforts to develop new protocols to differentiate in in vitro human mesenchymal stromal cells (hMSCs) into dopamine (DA) neurons have been reported. We have formulated NeuroForsk 2.0 medium containing fibroblast growth factor type beta (FGFb), brain-derived neurotrophic factor (BDNF), melatonin, purmorphamine, and forskolin. We report for the first time that menstrual stromal cells (MenSCs) cultured in NeuroForsk 2.0 medium for 7 days transdifferentiated into DA-like neurons (DALNs) expressing specific DA lineage markers tyrosine hydroxylase-positive cells (TH+) and DA transporter-positive (DAT+) cells and were responsive to DA-induced transient Ca²⁺ influx. To test the usefulness of this medium, DALNs were exposed to rotenone (ROT), a naturally occurring organic neurotoxin used extensively to chemically induce an in vitro model of Parkinson’s disease (PD), which is a movement disorder characterized by the specific loss of DA neurons. We wanted to determine whether ROT induces apoptotic cell death and autophagy pathway under acute or chronic conditions in DALNs. Here, we report that acute ROT exposure induced several molecular changes in DALNS. ROT induced a loss of mitochondrial membrane potential (ΔΨ_m), high expression of parkin (PRKN), and high colocalization of dynamin-related protein 1 (DRP1) with the mitochondrial translocase of the outer membrane of mitochondria 20 (TOMM20) protein. Acute ROT also induced the appearance of DJ-1Cys¹⁰⁶-SO₃, as evidenced by the generation of H₂O₂ and oxidative stress (OS) damage. Remarkably, ROT triggered the phosphorylation of leucine-rich repeat kinase 2 (LRRK2) at residue Ser⁹³⁵ and phosphorylation of α-Syn at residue Ser¹²⁹, a pathological indicator. ROT induced the accumulation of lipidated microtubule-associated protein 1B-light chain 3 (LC3B), a highly specific marker of autophagosomes. Finally, ROT induced cleaved caspase 3 (CC3), a marker of activated caspase 3 (CASP3) in apoptotic DALNs compared to untreated DANLs. However, the chronic condition was better at inducing the accumulation of lysosomes than the acute condition. Importantly, the inhibitor of the LRRK2 kinase PF-06447475 (PF-475) almost completely blunted ROT-induced apoptosis and reduced ROT-induced accumulation of lysosomes in both acute and chronic conditions in DALNs. Our data suggest that LRRK2 kinase regulated both apoptotic cell death and autophagy in DALNs under OS. Given that defects in mitochondrial complex I activity are commonly observed in PD, ROT works well as a chemical model of PD in both acute and chronic conditions. Therefore, prevention and treatment therapy should be guided to relieve DALNs from mitochondrial damage and OS, two of the most important triggers in the apoptotic cell death of DALNs. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

13 pages, 2353 KiB

Open AccessArticle

Expression Pattern of Trace Amine-Associated Receptors during Differentiation of Human Pluripotent Stem Cells to Dopaminergic Neurons

by Nataliia V. Katolikova, Anastasia N. Vaganova, Daria D. Shafranskaya, Evgeniya V. Efimova, Anna B. Malashicheva and Raul R. Gainetdinov

Int. J. Mol. Sci. 2023, 24(20), 15313; https://doi.org/10.3390/ijms242015313 - 18 Oct 2023

Cited by 6 | Viewed by 1977

Abstract

Trace amine-associated receptors (TAARs), which were discovered only in 2001, are known to be involved in the regulation of a spectrum of neuronal processes and may play a role in the pathogenesis of a number of neuropsychiatric diseases, such as schizophrenia and others. We have previously shown that TAARs also have interconnections with the regulation of neurogenesis and, in particular, with the neurogenesis of dopamine neurons, but the exact mechanisms of this are still unknown. In our work we analyzed the expression of TAARs (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8 and TAAR9) in cells from the human substantia nigra and ventral tegmental areas and in human pluripotent stem cells at consecutive stages of their differentiation to dopaminergic neurons, using RNA sequencing data from open databases, and TaqMan PCR data from the differentiation of human induced pluripotent stem cells in vitro. Detectable levels of TAARs expression were found in cells at the pluripotent stages, and the dynamic of their expression had a trend of increasing with the differentiation and maturation of dopamine neurons. The expression of several TAAR types (particularly TAAR5) was also found in human dopaminergic neuron-enriched zones in the midbrain. This is the first evidence of TAARs expression during neuronal differentiation, which can help to approach an understanding of the role of TAARs in neurogenesis. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

14 pages, 3648 KiB

Open AccessArticle

Organ-Chips Enhance the Maturation of Human iPSC-Derived Dopamine Neurons

by Maria G. Otero, Shaughn Bell, Alexander H. Laperle, George Lawless, Zachary Myers, Marian A. Castro, Jaquelyn M. Villalba and Clive N. Svendsen

Int. J. Mol. Sci. 2023, 24(18), 14227; https://doi.org/10.3390/ijms241814227 - 18 Sep 2023

Cited by 3 | Viewed by 2362

Abstract

While cells in the human body function in an environment where the blood supply constantly delivers nutrients and removes waste, cells in conventional tissue culture well platforms are grown with a static pool of media above them and often lack maturity, limiting their utility to study cell biology in health and disease. In contrast, organ-chip microfluidic systems allow the growth of cells under constant flow, more akin to the in vivo situation. Here, we differentiated human induced pluripotent stem cells into dopamine neurons and assessed cellular properties in conventional multi-well cultures and organ-chips. We show that organ-chip cultures, compared to multi-well cultures, provide an overall greater proportion and homogeneity of dopaminergic neurons as well as increased levels of maturation markers. These organ-chips are an ideal platform to study mature dopamine neurons to better understand their biology in health and ultimately in neurological disorders. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Figure 1

Review

Jump to: Research

20 pages, 1105 KiB

Open AccessReview

The Formation and Function of the VTA Dopamine System

by Guoqiang Hou, Mei Hao, Jiawen Duan and Ming-Hu Han

Int. J. Mol. Sci. 2024, 25(7), 3875; https://doi.org/10.3390/ijms25073875 - 30 Mar 2024

Cited by 16 | Viewed by 6874

Abstract

The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson’s disease, Huntington’s disease, major depression, schizophrenia, and drug addiction. The ventral tegmental area (VTA) has been identified as an important relay nucleus that modulates homeostatic plasticity in the midbrain dopamine system. Due to the complexity of synaptic transmissions and input–output connections in the VTA, the structure and function of this crucial brain region are still not fully understood. In this review article, we mainly focus on the cell types, neurotransmitters, neuropeptides, ion channels, receptors, and neural circuits of the VTA dopamine system, with the hope of obtaining new insight into the formation and function of this vital brain region. Full article

(This article belongs to the Special Issue Development of Dopaminergic Neurons 3.0)

► Show Figures

Journal Menu

Journal Browser

Development of Dopaminergic Neurons 3.0

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issues

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI