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Molecular Psychiatry May 2023Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem...
Dopaminergic neurons are critical to movement, mood, addiction, and stress. Current techniques for generating dopaminergic neurons from human induced pluripotent stem cells (hiPSCs) yield heterogenous cell populations with variable purity and inconsistent reproducibility between donors, hiPSC clones, and experiments. Here, we report the rapid (5 weeks) and efficient (~90%) induction of induced dopaminergic neurons (iDANs) through transient overexpression of lineage-promoting transcription factors combined with stringent selection across five donors. We observe maturation-dependent increase in dopamine synthesis and electrophysiological properties consistent with midbrain dopaminergic neuron identity, such as slow-rising after- hyperpolarization potentials, an action potential duration of ~3 ms, tonic sub-threshold oscillatory activity, and spontaneous burst firing at a frequency of ~1.0-1.75 Hz. Transcriptome analysis reveals robust expression of genes involved in fetal midbrain dopaminergic neuron identity. Specifically expressed genes in iDANs, as well as those from isogenic induced GABAergic and glutamatergic neurons, were enriched in loci conferring heritability for cannabis use disorder, schizophrenia, and bipolar disorder; however, each neuronal subtype demonstrated subtype-specific heritability enrichments in biologically relevant pathways, and iDANs alone were uniquely enriched in autism spectrum disorder risk loci. Therefore, iDANs provide a critical tool for modeling midbrain dopaminergic neuron development and dysfunction in psychiatric disease.
Topics: Humans; Dopaminergic Neurons; Autism Spectrum Disorder; Reproducibility of Results; Induced Pluripotent Stem Cells; Mesencephalon
PubMed: 34493831
DOI: 10.1038/s41380-021-01273-0 -
Medecine Sciences : M/S 2016Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should... (Review)
Review
Since the work of Johnson and North, it is known that opiates increase the activity of dopaminergic neurons by a GABA neuron-mediated desinhibition. This model should however be updated based on recent advances. Thus, the neuroanatomical location of the GABA neurons responsible for this desinhibition has been recently detailed: they belong to a brain structure in continuity with the posterior part of the ventral tegmental area and discovered this past decade. Other data also highlighted the critical role played by glutamatergic transmission in the opioid regulation of dopaminergic neuron activity. During protracted opiate withdrawal, the inhibitory/excitatory balance exerted on dopaminergic neurons is altered. These results are now leading to propose an original hypothesis for explaining the impact of protracted opiate withdrawal on mood.
Topics: Animals; Brain; Dopaminergic Neurons; GABAergic Neurons; Humans; Opiate Alkaloids; Synaptic Transmission; Ventral Tegmental Area
PubMed: 27406773
DOI: 10.1051/medsci/20163206026 -
International Journal of Molecular... Apr 2022The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson's disease (PD), and it is triggered by different factors, including mitochondrial... (Review)
Review
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.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra; alpha-Synuclein
PubMed: 35562898
DOI: 10.3390/ijms23094508 -
Food and Chemical Toxicology : An... Jun 2022Activated microglia play an active role in the pathogenesis of PD and paraquat (PQ) induces PD. The study was to understand the time relationship between microglial...
Activated microglia play an active role in the pathogenesis of PD and paraquat (PQ) induces PD. The study was to understand the time relationship between microglial activation and dopaminergic neuron loss in the substantia nigra (SN) of PQ-induced PD mice. Male C57BL/6 mice were injected intraperitoneally with PQ, twice a week for six weeks. Some mice underwent behavioral assessments each week and were sacrificed for SN tissues, in which histopathological analysis, dopaminergic neuron loss, microglial activation and phenotypic characteristics were evaluated. The results showed that motor retardation, coordination disorders and limb stiffness occurred four weeks after PQ exposure, as well as the degeneration and loss of dopaminergic neurons in the SN. Activated microglia and increased CD68 expression appeared two weeks after PQ exposure in time-dependent manners. Increased CD86 and decreased CD206 expression were observed four weeks after PQ exposure, accompanied by increased TNF-α and IL-6 levels and decreased IL-10 and TGF-β levels. These results indicate that PQ can activate microglia in vivo, and microglial activation precedes neuronal loss in the SN. Activated microglia are characterized by mixed M1/M2 polarization in the early stage and M1 polarization in the late stage of PQ-induced PD development.
Topics: Animals; Dopamine; Dopaminergic Neurons; Male; Mice; Mice, Inbred C57BL; Microglia; Nerve Degeneration; Paraquat; Parkinson Disease; Substantia Nigra
PubMed: 35430334
DOI: 10.1016/j.fct.2022.113018 -
Advances in Experimental Medicine and... 2020Parkinson's disease (PD) is one of the most common neurodegenerative diseases caused by specific degeneration and loss of dopamine neurons in substantia nigra of the...
Parkinson's disease (PD) is one of the most common neurodegenerative diseases caused by specific degeneration and loss of dopamine neurons in substantia nigra of the midbrain. PD is clinically characterized by motor dysfunctions and non-motor symptoms. Even though the dopamine replacement can improve the motor symptoms of PD, it cannot stop the neural degeneration and disease progression. Electrical deep brain stimulation (DBS) to the specific brain areas can improve the symptoms, but it eventually loses the effectiveness. Stem cell transplantation provides an exciting potential for the treatment of PD. Current available cell sources include neural stem cells (NSCs) from fetal brain tissues, human embryonic stem cells (hESCs) isolated from blastocyst, and induced pluripotent stem cells (iPSCs) reprogrammed from the somatic cells such as the fibroblasts and blood cells. Here, we summarize the research advance in experimental and clinical studies to transplant these cells into animal models and clinical patients, and specifically highlight the studies to use hESCs /iPSCs-derived dopaminergic precursor cells and dopamine neurons for the treatment of PD, at last propose future challenges for developing clinical-grade dopaminergic cells for treating the PD.
Topics: Animals; Dopaminergic Neurons; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Parkinson Disease; Stem Cell Transplantation
PubMed: 33105493
DOI: 10.1007/978-981-15-4370-8_3 -
ELife Apr 2018Most neurogenesis in the mammalian brain is completed embryonically, but in certain areas the production of neurons continues throughout postnatal life. The functional...
Most neurogenesis in the mammalian brain is completed embryonically, but in certain areas the production of neurons continues throughout postnatal life. The functional properties of mature postnatally generated neurons often match those of their embryonically produced counterparts. However, we show here that in the olfactory bulb (OB), embryonic and postnatal neurogenesis produce functionally distinct subpopulations of dopaminergic (DA) neurons. We define two subclasses of OB DA neuron by the presence or absence of a key subcellular specialisation: the axon initial segment (AIS). Large AIS-positive axon-bearing DA neurons are exclusively produced during early embryonic stages, leaving small anaxonic AIS-negative cells as the only DA subtype generated via adult neurogenesis. These populations are functionally distinct: large DA cells are more excitable, yet display weaker and - for certain long-latency or inhibitory events - more broadly tuned responses to odorant stimuli. Embryonic and postnatal neurogenesis can therefore generate distinct neuronal subclasses, placing important constraints on the functional roles of adult-born neurons in sensory processing.
Topics: Animals; Axon Initial Segment; Dopaminergic Neurons; Mice, Inbred C57BL; Neurogenesis; Olfactory Bulb; Phenotype
PubMed: 29676260
DOI: 10.7554/eLife.32373 -
Nature Communications Mar 2022The prefrontal cortex is involved in goal-directed behavior. Here, we investigate circuits of the PFC regulating motivation, reinforcement, and its relationship to...
The prefrontal cortex is involved in goal-directed behavior. Here, we investigate circuits of the PFC regulating motivation, reinforcement, and its relationship to dopamine neuron activity. Stimulation of medial PFC (mPFC) neurons in mice activated many downstream regions, as shown by fMRI. Axonal terminal stimulation of mPFC neurons in downstream regions, including the anteromedial thalamic nucleus (AM), reinforced behavior and activated midbrain dopaminergic neurons. The stimulation of AM neurons projecting to the mPFC also reinforced behavior and activated dopamine neurons, and mPFC and AM showed a positive-feedback loop organization. We also found using fMRI in human participants watching reinforcing video clips that there is reciprocal excitatory functional connectivity, as well as co-activation of the two regions. Our results suggest that this cortico-thalamic loop regulates motivation, reinforcement, and dopaminergic neuron activity.
Topics: Animals; Axons; Dopaminergic Neurons; Goals; Humans; Mice; Neural Pathways; Prefrontal Cortex; Thalamus
PubMed: 35296648
DOI: 10.1038/s41467-022-28892-7 -
Journal of Neurochemistry May 2022
Topics: Dopamine; Dopaminergic Neurons; Mesencephalon
PubMed: 35129216
DOI: 10.1111/jnc.15580 -
Development (Cambridge, England) Jan 2018Treating neurodegenerative diseases with cell transplantation has been within reach since the first pioneering clinical trials in which dopamine neuron progenitors from... (Review)
Review
Treating neurodegenerative diseases with cell transplantation has been within reach since the first pioneering clinical trials in which dopamine neuron progenitors from the fetal brain were transplanted to individuals with Parkinson's disease. However, the use of fetal tissue is problematic in terms of low availability and high variability, and it is also associated with ethical concerns that vary between countries. For decades, the field has therefore investigated new scalable source of therapeutic cells from stem cells or via reprogramming. Now it is possible to generate authentic midbrain dopaminergic neurons from pluripotent stem cells and clinical trials using such cells are rapidly approaching.
Topics: Animals; Cell- and Tissue-Based Therapy; Dopaminergic Neurons; Humans; Neural Stem Cells; Parkinson Disease; Stem Cell Transplantation
PubMed: 29311261
DOI: 10.1242/dev.156117 -
Medical Archives (Sarajevo, Bosnia and... Aug 2021Recent advances in stem cell technologies have rekindled an interest in the use of cell therapies to treat patients with Parkinson's disease. Although the...
BACKGROUND
Recent advances in stem cell technologies have rekindled an interest in the use of cell therapies to treat patients with Parkinson's disease. Although the transplantation of dopaminergic mesencephalic human fetal brain tissue has previously been reported in the treatment of patients with Parkinson's disease, this method is limited by the availability of tissue obtained from each human embryo.
OBJECTIVE
Our study aimed to isolate, culture, proliferate, and differentiate dopaminergic neurons from human neuroepithelial stem cells obtained from embryo reduction procedures performed in multifetal pregnancies following in vitro fertilization.
MATERIALS AND METHODS
A total of 201 human embryos were dissected for isolation and culture of neuroepithelial stem cells for proliferation and differentiation into dopaminergic neurons. All embryos were obtained from embryo reduction procedures performed in multifetal pregnancies after in vitro fertilization treatments.
RESULTS
Human neuroepithelial stem cells were isolated and cultured from embryos from 6.0 to 8.0 weeks. Neuroepithelial stem cells were successfully isolated, proliferated, and differentiated into dopaminergic neurons. The cells adhered to the surfaces of cell culture plates after 2 days and could be proliferated and differentiated into neurons within 4 days. Cultured cells expressed the dopaminergic marker tyrosine hydroxylase after 6 days, suggesting that these cells were successfully differentiated into dopaminergic neurons.
CONCLUSION
The successful isolation, culture, proliferation, and differentiation of human dopaminergic neurons from embryo reductions performed for multifetal pregnancies after in vitro fertilization suggests that this pathway may serve as a potential source of cell therapy materials for use in the treatment of Parkinson's disease.
Topics: Cell Differentiation; Cell Proliferation; Cells, Cultured; Dopaminergic Neurons; Female; Fertilization in Vitro; Humans; Pregnancy; Pregnancy Reduction, Multifetal; Stem Cells
PubMed: 34759448
DOI: 10.5455/medarh.2021.75.280-285